Azetidine derivatives, their preparation and medicaments containing them

ABSTRACT

Disclosed are azetidine derivatives of formula:  
                 
their optical isomers, their salts, their preparation and medicaments containing them.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Application Ser. No.10/870.274, filed Jun. 14, 2004, which is a continuation of U.S.Application Ser. No. 10/320,344, filed Dec. 16, 2002, which is acontinuation of U.S. Application Ser. No. 09/803,723, filed Mar. 9,2001, now U.S. Pat. No. 6,518,264 which is a continuation ofInternational Application No. PCT/FR99/02147, filed Sep. 9, 1999, which,in turn, claims the benefit of U.S. Provisional Application No.60/119929, filed on Feb. 12, 1999, and of French Patent ApplicationFR98/11342, filed on Sep. 11, 1998.

SUMMARY OF THE INVENTION

The present invention relates to azetidine derivatives of formula:

their optical isomers, their salts, their preparation and medicamentscontaining them, as well as to methods of using these derivatives totreat a variety of medical conditions and disorders.

DETAILED DESCRIPTION

In formula (I),

-   R represents a chain-   R₁ represents a methyl or ethyl radical,-   R₂ represents either an aromatic chosen from phenyl, naphthyl or    indenyl, these aromatics being nonsubstituted or substituted with    one or more halogens, alkyl, alkoxy, —CO-alk, hydroxyl, —COOR₅,    formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy,    nitro, —NR₆R₇, —CO—NH—NR₆R₇, —N(alk)COOR₈, cyano, —CONHR₉,    —CO—NR₁₆R₁₇, alkylsulfanyl, hydroxyalkyl, —O-alk-NR₁₂R₁₃ or    alkylthioalkyl or a heteroaromatic chosen from the benzofuryl,    benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,    2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl,    isochromanyl, isoquinolyl, pyridyl, quinolyl,    1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl,    thiazolyl, or thienyl rings, it being possible for these    heteroaromatics to be nonsubstituted or substituted with a halogen,    alkyl, alkoxy, —COOR₅, trifluoromethyl, trifluoromethylsulfanyl,    trifluoromethoxy, nitro, —NR₆R₇, —CO—NH—NR₆R₇, cyano, —CONHR₉,    alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,-   R₃ and R₄, which are identical or different, represent either an    aromatic chosen from phenyl, naphthyl or indenyl, these aromatics    being nonsubstituted or substituted with one or more halogens,    alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy,    nitro, —CO-alk, cyano, —COOR₅, —CONR₁₀R₁₁, —CO—NH—NR₆R₇,    alkylsulfanyl, hydroxyalkyl, -alk-NR₆R₇ or alkylthioalkyl; or a    heteroaromatic chosen from the benzofuryl, benzothiazolyl,    benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,    2,3-dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl,    quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl, or thienyl    rings, it being possible for these heteroaromatics to be    nonsubstituted or substituted with a halogen, alkyl, alkoxy,    hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, —COOR₅,    —CO—NH—NR₆R₇, —CONR₁₀R₁₁, -alk-NR₆R₇, alkylsulfanyl, hydroxyalkyl or    alkylthioalkyl;-   R₅ is an alkyl or phenyl radical which is optionally substituted    with one or more halogen atoms,-   R₆ and R₇, which are identical or different, represent a hydrogen    atom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk    or hydroxyalkyl radical or alternatively R₆ and R₇ together form    with the nitrogen atom to which they are attached a 3- to    10-membered saturated or unsaturated mono- or bicyclic heterocycle    optionally containing another heteroatom chosen from oxygen, sulfur    and nitrogen and being optionally substituted with one or more    alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo,    hydroxyalkyl, -alk-O-alk or —CO—NH₂ radicals,-   R₈ represents an alkyl radical,-   R₉ represents a hydrogen atom or an alkyl radical or an alkyl    radical substituted with a dialkylamino, phenyl, cycloalkyl    (optionally substituted with —COOalk) or a 3- to 10-membered    saturated or unsaturated mono- or bicyclic heterocycle optionally    containing one or more heteroatoms chosen from oxygen, sulfur and    nitrogen and being optionally substituted with one ore more alkyl    radicals,-   R₁₀ and R₁₁, which are identical or different, represent a hydrogen    atom or an alkyl radical or alternatively R₁₀ and R₁₁ together form    with the nitrogen atom to which they are attached a 3- to    10-membered saturated mono- or bicyclic heterocycle optionally    containing another heteroatom chosen from oxygen, sulfur and    nitrogen and being optionally substituted with an alkyl radical,-   R₁₂ and R₁₃, which are identical or different, represent a hydrogen    atom or an alkyl or cycloalkyl radical or alternatively R₁₂ and R₁₃    together form with the nitrogen atom to which they are attached a 3-    to 10-membered saturated mono- or bicyclic heterocycle optionally    containing another heteroatom chosen from oxygen, sulfur and    nitrogen and being optionally substituted with an alkyl, —COalk,    —COOalk, —CO—NHalk, —CS—NHalk or —CO-alk-NR₁₄R₁₅ radical or a 3- to    10-membered saturated mono- or bicyclic heterocycle containing a    heteroatom chosen from oxygen, sulfur and nitrogen,-   R₁₄ and R₁₅, which are identical or different, represent a hydrogen    atom or an alkyl or —COOalk radical,-   R₁₆ and R₁₇ together form with the nitrogen atom to which they are    attached a 3- to 10-membered saturated mono- or bicyclic heterocycle    optionally containing another heteroatom chosen from oxygen, sulfur    and nitrogen,-   R′ represents a hydrogen atom or a —CO-alk radical, alk represents    an alkyl or alkylene radical.

In the preceding definitions and in those which follow, unless otherwisestated, the alkyl and alkylene radicals and portions and the alkoxyradicals and portions are in the form of a straight or branched chainand contain 1 to 6 carbon atoms.

Among the alkyl radicals, there may be mentioned methyl, ethyl,n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexylradicals. Among the alkoxy radicals, there may be mentioned methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, is-butoxy, sec-butoxy,tert-butoxy and pentyloxy radicals.

The term halogen comprises chlorine, fluorine, bromine and iodine.

When R₂ and/or R₃ and/or R₄ represent independently a substitutedphenyl, the latter is preferably mono-, di- or trisubstituted.

When R₆ and R₇ together form with the nitrogen atom to which they areattached a 3- to 10-membered saturated or unsaturated mono- or bicycleheterocycle, the latter is preferably an azetidinyl, pyrrolidinyl,piperazinyl, piperidyl, morpholinyl, imidazolyl, thiomorpholinyl orfuryl ring, these rings being optionally substituted with an alkyl,hydroxyalkyl, -alk-O-alk, —CONH₂, —COalk, —COOalk, oxo, —CSNHalk,—CONHalk or —CO-alk-NR₁₄R₁₅ radical and, in particular, with a methyl,ethyl, propyl, isobutyl, acetyl, N,N-dimethylaminomethylcarbonyl,methyloxycarbonyl, methylcarbamoyl, methylthiocarbamoyl,N-methylaminomethylcarbonyl,N-methyl-N-tertbutoxycarbonylaminomethylcarbonyl, oxo, —CSNHCH₃ or—CONHCH₃ radical.

When R₁₀ and R₁₁ together form with the nitrogen atom to which they areattached a 3- to 10-membered saturated mono- or bicyclic heterocycle,the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl,piperidyl, morpholinyl or thiomorpholinyl ring, these rings beingoptionally substituted with an alkyl.

When R₁₂ and R₁₃ form together with the nitrogen atom to which they areattached a 3- to 10-membered saturated mono- or bicyclic heterocycle,the latter is preferably an azetidinyl, pyrrolidinyl, piperazinyl,piperidyl, morpholinyl or thiomorpholinyl ring, these rings beingoptionally substituted with an alkyl, —COalk, —COOalk, —CO—NHalk,—CS—NHalk or —CO-alk-NR₁₄R₁₅ radical or a 3- to 10-membered saturatedmono- or bicyclic heterocycle containing a heteroatom chosen fromoxygen, sulfur and nitrogen, and, in particular, with a thiomorpholinylradical.

When R₁₆ and R₁₇ together from with the nitrogen atom to which they areattached a 3- to 10-membered saturated mono- or bicyclic heterocycle,the latter is preferably a piperidyl ring.

When R₉ represents an alkyl radical substituted with a 3- to 10-memberedsaturated or unsaturated mono-or bicyclic heterocycle optionallycontaining one or more heteroatoms chosen from oxygen, sulfur andnitrogen, the latter is preferably a pyrrolidinyl, tetrahydrofuryl,morpholinyl or pyrrolyl ring, these rings being optionally substitutedwith one or more alkyl radicals.

The compounds of formula (I) may be provided in the form of enantiomersand diastereoisomers. These optical isomers and mixtures thereof formpart of the invention.

The compounds of formula (I) for which R represents a chain of formula(A) may be prepared by dehydration of a corresponding compound offormula (Ia)

in which R₁, R₂, R₃ and R₄ have the same meanings as in formula (I) andR″ represents a hydroxyl, methanesulfonyloxy or acetyloxy radical.

This dehydration is carried out by any method known to persons skilledin the art which makes it possible to dehydrate an alcohol or one of itsderivatives in order to obtain the corresponding alkene. Preferably,derivatives are used for which R″ is a methanesulfonyloxy or acetyloxyradical obtained from the corresponding derivative for which R″ is ahydroxyl radical by the action of methanesulfonyl chloride or acetylchloride, in an inert solvent such as pyridine, tetrahydrofuran,dioxane, a chlorinated solvent (dichloromethane or chloroform forexample), at a temperature between 5° C. and 20° C. and then the mediumis treated with a base such as an alkali metal hydroxide (sodiumhydroxide for example), an alkali metal carbonate (sodium or potassiumcarbonate for example), an amine such as a trialkylamine (triethylaminefor example), 4-dimethylaminopyridine,diaza-1,8-bicyclo[5.4.0]undec-7-ene, at a temperature of between 0° C.and the boiling temperature of the reaction mixture. Themethanesulfonyloxy and the acetyloxy may be isolated or otherwise.

The compounds of formula (I) for which R represents a chain (B) in whichR′ is a hydrogen atom may be prepared by reacting the derivativeR₁SO₂CH₂R₂ (II) for which R₁ and R₂ have the same meanings as in formula(I) with an azetidinone of formula:

in which R₃ and R₄ have the same meanings as in formula (I).

The procedure is generally carried out in an inert solvent such as anether (tetrahydrofuran for example), in the presence of a strong basesuch as lithium diisopropylamide, potassium tert-butoxide orn-butyllithium, at a temperature of between −70° C. and −15° C.

The derivatives of formula (II) may be obtained by application oradaptation of the methods described in the examples. In particular, theprocedure is carried out according to the following reaction schemes:

In these formulae Hal represents a halogen atom and, preferably,chlorine, bromine or iodine, R₁ and R₂ have the same meanings as informula (I).

The reaction (a) is generally carried out in an inert solvent such asdimethylformamide or a 1-4C aliphatic alcohol, at a temperature ofbetween 20 and 30° C.

The reaction (b) is carried out by any known method which makes itpossible to oxidize a sulfur-containing derivative without affecting therest of the molecule such as the methods described by M. MUDLICKY,Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). Forexample, the procedure is carried out by the action of an organic peroxyacid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonicacids, especially peroxybenzoic acid, 3-chloroperoxybenzoic acid,4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyaceticacid, peroxyformic acid or monoperoxyphtalic acid) or in organicperacids or a salt of such an acid (for example periodic or persulfuricacid), in an inert solvent such as a chlorinated solvent (chloroform ordichloromethane for example), at a temperature of between 0 and 25° C.It is also possible to use hydrogen peroxide or a periodate (sodiumperiodate for example), in an inert solvent such as 1-4C aliphaticalcohol (methanol or ethanol for example), water or a mixture of thesesolvents, at a temperature of between 0 and 20 C. It is also possible tocarry out the procedure using tert-butyl hydroperoxide in the presenceof titanium tetraisopropoxide in a 1-4C aliphatic alcohol (methanol orethanol for example) or a water-alcohol mixture, at a temperature closeto 25° C. or using oxone^(R) (potassium peroxymonosulfate), in a 1-4Caliphatic alcohol (methanol or ethanol for example), in the presence ofwater, acetic acid or sulfuric acid, at a temperature close to 20° C.

The reaction (c) is preferably carried out in an inert solvent such as a1-4C aliphatic alcohol (methanol or ethanol for example), at atemperature of between 20° C. and the boiling temperature of thereaction medium.

The derivatives of formula (IV) are commercially available or may beobtained by application or adaptation of the methods described in theexamples. In particular, the methylated derivative or the correspondingalcohol is halogenated using a halogenating agent, such as hydrobromicacid, in acetic acid, at a temperature close to 20° C. or N-bromo- orchlorosuccinimide in the presence of benzoyl peroxide, in an inertsolvent such as tetrachloromethane, at the boiling temperature of thereaction medium. The methylated derivatives or the correspondingalcohols are commercially available or may be obtained according to themethods described by BRINE G. A. et al, J. Heterocycl. Chem., 26, 677(1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the examples.

The azetidinones of formula (III) may be obtained by application oradaptation of the methods described by KATRITZKY A. R. et al, J.Heterocycl. Chem., 271 (1994) or DAVE P. R., J. Org. Chem., 61, 5453(1996) and in the examples. The procedure is generally carried outaccording to the following reaction scheme:

In these formulae, R₃ and R₄ have the same meanings as in formula (I)and X represents a chlorine or bromine atom.

In step A, the procedure is preferably carried out in an inert solventsuch as a 1-4C aliphatic alcohol (ethanol or methanol for example),optionally in the presence of an alkali metal hydroxide, at the boilingtemperature of the reaction medium.

In step B, the reduction is generally carried out using lithium aluminumhydride, in tetrahydrofuran at the boiling temperature of the reactionmedium.

In step C, the procedure is preferably carried out in an inert solventsuch as a 1-4C aliphatic alcohol (ethanol or methanol for example) inthe presence of sodium hydrogen carbonate, at a temperature of between20° C. and the boiling temperature of the reaction medium.

In step D, the oxidation is preferably carried out in DMSO, using thesulfurtrioxide-pyridine complex, at a temperature close to 20° C. orusing dimethyl sulfoxide, in the presence of oxalyl chloride andtriethylamine, at a temperature of between −70 and −50 °C.

In step E, the procedure is carried out according to the methoddescribed by GRISAR M. et al., in J. Med. Chem., 885 (1973). Themagnesium compound of the brominated derivative is formed and then thenitrile is reacted, in an ether such as ethyl ether, at a temperature ofbetween 0° C. and the boiling temperature of the reaction medium. Afterhydrolysis with an alcohol, the intermediate imine is reduced in situwith sodium borohydride at a temperature of between 0° C. and theboiling temperature of the reaction medium.

The R₃—CO—R₄ derivatives are commercially available or may be obtainedby application or adaptation of the methods described by KUNDER N. G. etal. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS J., Eur. J.Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546(1971); HURN N. K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al.,Tet. Lett., 24 (28) 2901 (1983); RIECKE R. D. et al., J. Org. Chem., 62(20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973);CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996);FR-96-2481 and JP-94-261393.

The R₃Br derivatives are commercially available or may be obtained byapplication or adaptation of the methods described by BRANDSMA L. etal., Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIRE M. et al.,Synth. Comm., 24 (1) 95 (1994); GODA H. et al., Synthesis, 9 849 (1992);BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).

The R₄CN derivatives are commercially available or may be obtained byapplication or adaptation of the methods described by BOUYSSOU P. etal., J. Het. Chem., 29 (4) 895 (1992); SUZUKIN N. et al., J. Chem. Soc.Chem. Comm. 1523 (1984); MARBURG S. et al., J. Het. Chem., 17 1333(1980); PERCEC V. et al., J. Org. Chem. 60 (21) 6895 (1995).

The compounds of formula (I) for which R represents a chain (B) in whichR′ is a hydrogen atom may also be prepared by action of a derivativeR₃CH(Br)R₄ (VI) for which R₃ and R₄ have the same meanings as in formula(I) with a derivative of formula:

in which R₁ and R₂ have the same meanings as in formula (I).

This reaction is generally carried out in the presence of a base such asan alkali metal carbonate (potassium carbonate for example), in an inertsolvent such as acetonitrile, at the boiling temperature of the reactionmedium.

The derivatives of formula (VI) are commercially available or may beobtained by application or adaptation of the method described byBACHMANN W. E., J. Am. Chem. Soc., 2135 (1933). Generally, thecorresponding alcohol R₃CHOHR₄ is brominated using hydrobromic acid, inacetic acid, at a temperature of between 0° C. and the boilingtemperature of the reaction medium.

The corresponding R₃CHOHR₄ alcohols are commercially available or may beobtained by application or adaptation of the methods described by PLASZA. C., et al., J. Chem. Soc. Chem. Comm., 527 (1972).

The derivatives of formula (VII) may be obtained by hydrolysis of aderivative of formula:

in which R₁ and R₂ have the same meanings as in formula (I).

This reaction is generally carried out using hydrochloric acid, in aninert solvent such as an ether (dioxane for example), at a temperatureclose to 20° C.

The derivatives of formula (VIII) are obtained by reacting vinylchloroformate with a corresponding compound of formula (I) for [lacuna]R represents a chain of formula (B). R′ represents a hydroxyl radical,R₃ and R₄ are phenyl radicals, in an inert solvent such as a chlorinatedsolvent (dichloromethane or chloroform for example), at a temperature ofbetween 0° C. and the boiling temperature of the reaction mixture.

The compounds of formula (I) for which R is a chain (B) in which R′ is a—CO-alk radical may be prepared by reacting a halide Hal-CO-alk in whichHal represents a halogen atom and, preferably, a chlorine atom and alkrepresents an alkyl radical with a corresponding compound of formula (I)for which R is a chain (B) in which R′ is a hydrogen atom.

This reaction is generally carried out in an inert solvent such astetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane orchloroform for example), at a temperature of between −50° C. and 20° C.,in the presence of n-butyllithium.

The compounds of formula (I) for which R₂ represents an aromatic or aheteroaromatic substituted with —NR₆R₇in which R₆ and R₇ each representa hydrogen atom may also be prepared by reducing a correspondingcompound of formula (I) for which R₂ represents an aromatic or aheteroaromatic substituted with nitro.

This reaction is carried out by any known method which makes it possibleto reduce a nitro to an amino without affecting the rest of themolecule. Preferably, iron is used in the presence of hydrochloric acidin a 1-4C aliphatic alcohol such as ethanol, at the boiling temperatureof the reaction medium.

The compounds of formula (I) for which R₂ represents an aromatic orheteroaromatic substituted with −COHNR₉ and/or R₃ and/or R₄ represent anaromatic or a heteroaromatic substituted with —CONR₁₀R₁₁ may also beprepared by reacting a corresponding compound of formula (I) for whichR₂ and/or R₃ and/or R₄ represent an aromatic or a heteroaromaticsubstituted with —COOR₅ for which R₅ is alkyl or phenyl optionallysubstituted with halogens with respectively an amine H₂NR₉ or HNR₁₀R₁₁for which R₉, R₁₀ and R₁₁ have the same meanings as in formula (I).

This reaction is generally carried out in an inert solvent such as achlorinated solvent (dichloromethane or chloroform for example) or a1-4C aliphatic alcohol (methanol or ethanol for example), at atemperature of between 0° C. and the boiling temperature of the reactionmixture.

The compounds of formula (I) for which R₂ represents an aromaticsubstituted with hydroxyl and/or R₃ and/or R₄ represent an aromatic or aheteroaromatic substituted with hydroxyl may also be prepared byhydrolysis of a corresponding compound of formula (I) for which R₂represents an aromatic substituted with alkoxy and/or R₃ and/or R₄represent an aromatic or a heteroaromatic substituted with alkoxy.

The reaction is carried out by any method of hydrolyzing an alkoxy to ahydroxyl without affecting the rest of the molecule. Preferably, thehydrolysis is carried out using boron tribromide, in a chlorinatedsolvent such as dichloromethane, at a temperature close to 20° C.

The compounds of formula (I) for which R₂ represents an aromaticsubstituted with —NR₆R₇ for which R₆ represents an alkyl radical and R₇represents a hydrogen atom may also be prepared by deprotecting acorresponding compound of formula (I) for which R₂ represents anaromatic substituted with an —N(alk)COOR₈ in which R₈ represents atert-butyl radical.

This reaction is generally carried out using hydrochloric acid, in asolvent such as dioxane at a temperature close to 20° C.

The compounds of formula (I) for which R₂ and/or R₃ and/or R₄ representan aromatic substituted with —COOR₅ may also be prepared byesterification of a derivative of formula:

for which R represents a chain C=C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R′₂, R₁,R′₂, R′₃ and R′₄ have the same meanings as the substituents R₁, R₂, R₃and R₄ of formula (I) with the proviso that at least one of thesubstituents R′₂, R′₃ and R′₄ represents an aromatic or a heteroaromaticsubstituted with carboxyl, using a derivative of formula R₅OH for whichR₅ is alkyl or phenyl optionally substituted with one or more halogens.

When R₅ is alkyl, this reaction is generally carried out in the presenceof an inorganic acid (sulfuric acid for example), at a temperature ofbetween 20° C. and the boiling temperature of the reaction medium. WhenR₅ is optionally substituted phenyl, this reaction is preferably carriedout in the presence of a carbodiimide(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide orN,N′-dicyclohexylcarbodiimide for example), in an inert solvent such asan imide (dimethylformamide) or a chlorinated solvent (methylenechloride, 1,2-dichloroethane or chloroform for example), at atemperature of between 0° C. and the boiling temperature of the reactionmixture.

The derivatives of formula (IX) for which R represents a chainC=C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R′₂, R′, R₁, R′₂, R′₃ and R′₄ have thesame meanings as the substituents R′. R₁, R₂, R₃ and R₄ of the formula(I) with the proviso that at least one of the substituents R′₂, R′₃ andR′₄ represents an aromatic or a heteroaromatic substituted with carboxylmay be obtained according to the methods described above for thepreparation of the compounds of formula (I) from the correspondingintermediates and in particular according to the method described inExample 29.

The compounds of formula (I) for which R₂ and/or R₃ and/or R₄ representan aromatic or a heteroaromatic substituted with alkylthioalkyl may alsobe prepared by reaction of a derivative of formula (IX) for which Rrepresents a chain C=C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R′₂, R′, R₁, R′₂, R′₃and R′₄ have the same meanings as the substituents R′, R₁, R₂, R₃ and R₄of the formula (I) with the proviso that at least one of thesubstituents R′₂, R′₃ and R′₄ represents an aromatic or a heteroaromaticsubstituted with haloalkyl with sodium alkylthiolate.

This reaction is generally carried out in an inert solvent such as anamide (dimethylformamide for example), at a temperature close to 20° C.

The derivatives of the formula (IX) for which R represents a chainC=C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R′₂, R′, R₁, R′₂, R′₃ and R′₄ have thesame meanings as the substituents R′, R₁, R₂, R₃ and R₄ of the formula(I) with the proviso that at least one of the substituents R′₂, R′₃ andR′₄ represents an aromatic or a heteroaromatic substituted withhaloalkyl may be obtained by reacting a phosphorus trihalide (preferablyphosphorus tribromide) with a corresponding compound of formula (I) forwhich R₂ and/or R₃ and/or R₄ represent an aromatic or a heteroaromaticsubstituted with hydroxyalkyl, in an inert solvent such as a chlorinatedsolvent (carbon tetrachloride or chloroform for example), at atemperature close to 20° C.

The compounds of formula (I) for which R₂ and/or R₃ and/or R₄ representan aromatic substituted with hydroxyalkyl in which the alkyl containsone carbon atom may also be prepared by reducing a compound of formula(I) for which at least one of the substituents R₂, R₃ and R₄ representsan aromatic substituted with formyl.

This reaction is generally carried out using sodium borohydride, in a1-4C aliphatic alcohol (methanol or ethanol for example), at atemperature close to 0° C.

The compounds of formula (I) for which R₃ and/or R₄ represents anaromatic substituted with -alk-NR₆R₇ for which alk is an alkylcontaining one carbon atom may also be prepared by reacting a compoundof formula (I) for which at least one of the substituents R₃ and R₄represents an aromatic substituted with formyl with an amine HNR₆R₇ inwhich R₆ and R₇ have the same meanings as in formula (I).

This reaction is generally carried out in an inert solvent such as achlorinated solvent (dichloroethane for example), at a temperature closeto 20° C. in the presence of sodium triacetoxyborohydride or sodiumcyanoborohydride.

The compounds of formula (I) for which R₂ represents an aromatic or aheteroaromatic substituted with —CONHR₉ and/or R₃ and/or R₄ representsan aromatic or heteroaromatic substituted with —CO—NR₁₀R₁₁ may also beprepared by reacting a derivative of formula (IX) for which R representsa chain C=C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R′₂, R′, R₁, R′₂, R′₃ and R′₄have the same meanings as the substituents R′, R₁, R₂, R₃ and R₄ of theformula (I) with the proviso that at least one of the substituents R′₂,R′₃ and R′₄ represents an aromatic or a heteroaromatic substituted withcarboxyl with respectively an amine H₂NR₉ or HNR₁₀R₁₁ in which R₉, R₁₀and R₁₁ have the same meanings as in formula (I).

This reaction is preferably carried out in the presence of a condensingagent which is used in peptide chemistry such as a carbodiimide (forexample 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide orN,N′-dicyclohexylcarbodiimide) or N,N′-carbonyldiimidazole, in an inertsolvent such as an ether (tetrahydrofuran or dioxane for example), anamide (dimethylformamide) or a chlorinated solvent (methylene chloride,1,2-dichloroethane or chloroform for example) at a temperature ofbetween 0° C. and the boiling temperature of the reaction mixture, orafter prior binding of the acid to a resin of the TFP type of formula:

in which S represents an aminopolystyrene resin, in an inert solventsuch as dimethylformamide, in the presence of 4-dimethylaminopyridine,at a temperature close to 20° C. The binding to the resin is generallycarried out in dimethylformamide, in the presence of4-dimethylaminopyridine and 1,3-diisopropylcarbodiimide, at atemperature close to 20° C.

The compounds of formula (I) for which R₂ and/or R₃ and/or R₄ representan aromatic or a heteroaromatic substituted with —CO—NH—NR₆R₇ may alsobe prepared by reacting a corresponding compound of formula (I) forwhich R₂ and/or R₃ and/or R₄ represent an aromatic or a heteroaromaticsubstituted with —COOR₅ and/or R₄ represent an alkyl or phenyl radicaloptionally substituted with halogens, with a hydrazine H₂N—NR₆R₇ forwhich R₆ and R₇ have the same meanings as in formula (I).

This reaction is generally carried out in an inert solvent such asdimethylformamide, at a temperature close to 20° C.

The compounds of formula (I) for which R₂ represents an aromatic or aheteroaromatic substituted with —CO—NHR₉ in which R₉ represents ahydrogen atom and/or R₃ and/or R₄ represent an aromatic or aheteroaromatic substituted with —CO—NR₁₀R₁₁ in which R₁₀ and R₁₁ arehydrogen atoms may also be prepared by hydrolysis of a correspondingcompound of formula (I) for which R₂ and/or R₃ and/or R₄ represent anaromatic or a heteroaromatic substituted with cyano.

This reaction is carried out by any known method which makes it possibleto pass from a nitrile to the corresponding carbamoyl without affectingthe rest of the molecule. Preferably, the procedure is carried out usinghydrochloric acid, in acetic acid, at a temperature close to 20° C.

The compounds of formula (I) for which R₂ represents an aromaticsubstituted with —O-alk-NR₁₂R₁₃ may also be prepared by reacting aderivative of formula (IX) for which R represents a chain C=C(SO₂R₁)-R′₂or C(OR′)CH(SO₂R₁)R′₂, R′, R₁, R₂′, R₃′ and R₄′ have the same meaningsas the substituents R′, R₁R₂, R₃ and R₄ of the formula (I) with theproviso that at least one of the substituents R₂′, R₃′ or R₄′ representsan aromatic substituted with —O-alk-Hal in which alk represents an alkylradical and Hal represents a halogen atom and, preferably, a chlorine orbromine atom, with an amine HNR₁₂R₁₃ in which R₁₂R₁₃ have the samemeanings as in formula (I).

This reaction is generally carried out in an inert solvent such asacetonitrile, in the presence of an alkali metal carbonate (potassiumcarbonate for example), at a temperature close to 20° C.

The derivatives of formula (IX) for which R represents a chainC=C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R′₂, R′, R₁, R₂′, R₃′ and R₄′ have thesame meanings as the substituents R′, R₁, R₂, R₃ and R₄ of the formula(I) with the proviso that at least one of the substituents R₂′, R₃′ orR₄′ represents an aromatic substitutes with —O-alk-Hal in which alkrepresents an alkyl radical and Hal represents a halogen atom may beobtained by reacting a corresponding compound of formula (I) for whichR₂ represents an aromatic substituted with hydroxide with an Hal-alk-Halderivative in which Hal represents a halogen.

This reaction is generally carried out in an inert solvent such as aketone (methyl ethyl ketone for example), in the presence of a base suchas a alkali metal carbonate (potassium carbonate for example), at theboiling temperature of the reaction medium.

The compounds of formula (I) for which R₃ and/or R₄ represents anaromatic substituted with -alk-NR₆R₇ may also be prepared by reacting aderivative of formula (IX) for which R represents a chain C=C(SO₂R₁)R′₂or C(OR′)CH(SO₂R₁)R′₂, R′, R₁, R₂′, R₃′ and R₄′ have the same meaningsas the substituents R′, R₁, R₂, R₃ and R₄ of the formula (I) with theproviso that at least one of the substituents R₃′ or R₄′ represents asubstituted aromatic -alk-Cl in which alk represents an alkyl radicalwith an amine HNR₆R₇ in which R₆R₇ have the same meanings as in formula(I).

This reaction is generally carried out in an inert solvent such as achlorinated solvent (dichloromethane for example), optionally in thepresence of a nitrogen base such as dimethylaminopyridine,diisopropylethylamine, at a temperature of between 5 and 25° C.

The derivatives of formula (IX) for which R represents a chainC=C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R₂, R′, R₁, R₂′, R₃′ and R₄′ have thesame meanings as the substituents R′, R₁, R₂, R₃ and R₄ of the formula(I) with the proviso that at least one of the substituents R₃′ or R₄′represents an aromatic substituted with —-alk-Cl may be obtained byreacting thionyl chloride with a corresponding compound of formula (I)for which at least one of the substituents R₃ or R₄ represents anaromatic substituted with one or more hydroxyalkyl radicals.

This reaction is generally carried out in an inert solvent such as achlorinated solvent (dichloromethane for example), at a temperature ofbetween 10 and 30° C.

The compounds of formula (I) for which R represents a chain B, R′represents a hydrogen atom and R₃ and/or R₄ represents an aromaticsubstituted with hydroxyalkyl in which the alkyl residue contains onecarbon atom may also be prepared by reacting diisobutylaluminum hydridewith a corresponding compound of formula (I) for which R represents achain B, R′ represents a hydrogen atom and R₃ and/or R₄ represents anaromatic substituted with one or more —COOR₅ radicals, in which R₅ is analkyl radical.

This reaction is generally carried out in toluene, at a temperature ofbetween −30° C. and 0° C.

The compounds of formula (I) for which R₂ represents a phenyl radicalsubstituted with —NR₆R₇ representing a 1-piperazinyl ring substituted atthe 4 position with an alkyl radical may also be prepared by reacting acorresponding compound of formula (I) for which R₂ represents a phenylradical substituted with a radical —NR₆R₇ representing a 1-piperazinylring with an alk-CHO derivative in which alk represents a straight- orbranched-chain alkyl radical containing 1 to 6 carbon atoms.

This reaction is generally carried out in an inert solvent such as achlorinated solvent (dichloroethane or chloroform for example), in thepresence of NaBH(OCOCH₃)₃, at a temperature close to 20° C.

The compounds of formula (I) for which R₂ represents a phenyl radicalsubstituted with —NR₆R₇ representing a 1-piperazinyl ring substituted atthe 4 position with a radical —COOalk may also be prepared by reacting acorresponding compound of formula (I) for which R₂ represents a phenylradical substituted with a radical —NR₆R₇ representing a 1-piperazinylring with a derivative of formula Hal-COOalk in which alk represents analkyl radical and Hal represents a halogen atom and, preferably, achlorine atom.

This reaction is generally carried out in pyridine, at a temperatureclose to 20° C.

The compounds of formula (I) for which R₂ represents a phenyl radicalsubstituted with —NR₆R₇ representing a 1-piperazinyl ring substituted atthe 4 position with a radical —CO—NHalk or —CS—NHalk may also beprepared by reacting a corresponding compound of formula (I) for whichR₂ represents a phenyl radical substituted with —NR₆R₇ representing a1-piperazinyl ring with a derivative of formula Y=C=Nalk in which alkrepresents a straight- or branched-chain alkyl radical containing 1 to 6carbon atoms and Y represents a sulfur or oxygen atom.

This reaction is generally carried out in an inert solvent such as achlorinated solvent (dichloromethane for example), at a temperatureclose to 20° C.

The compounds of formula (I) for which R₂ represents a phenyl radicalsubstituted with —NR₆R₇ representing a 1-piperazinyl ring substituted atthe 4 position with a radical —CO-alk-NR₁₄R₁₅ may also be prepared byreacting a corresponding compound of formula (I) for which R₂ representsa phenyl radical substituted with a radical —NR₆R₇ representing a1-piperazinyl ring with an acid of formula R₁₅R₁₄N-alk-COOH in which alkrepresents an alkyl radical and R₁₄ and R₁₅ have the same meanings as informula (I), optionally followed by deprotection of the product forwhich R₁₄ is a tert-butoxycarbonyl radical in order to obtain thecompounds for which R₁₄ is a hydrogen atom.

This reaction is generally carried out in an inert solvent such as achlorinated solvent (dichloroethane for example), at a temperature closeto 20° C. The deprotection is carried out using formic acid at atemperature close to 20° C.

The compounds of formula (I) for which R₂ represents a phenyl radicalsubstituted with —NR₆R₇ representing a 1-piperazinyl ring substituted atthe 4 position with a radical —CO-alk in which alk represents a methylradical may also be prepared by reacting a corresponding compound offormula (I) for which R₂ represents a phenyl radical substituted with aradical —NR₆R₇representing a 1-piperazinyl ring with acetic anhydride.

This reaction is generally carried out in the presence of pyridine, at atemperature close to 20° C.

It is understood for persons skilled in the art that, to carry out theprocess according to the invention which are described above, it may benecessary to introduce groups protecting amino, hydroxyl and carboxylfunctions in order to avoid side reactions. These groups are those whichallow removal without affecting the rest of the molecule. As examples ofgroups protecting the amino function, there may be mentioned tert-butylor methylcarbamates which may be regenerated using iodotrimethylsilaneor allyl using palladium catalysts. As examples of groups protecting thehydroxyl function, there may be mentioned triethylsilyl andtert-butyldimethylsilyl which may be regenerated usingtetrabutylammonium fluoride or alternatively asymmetric acetals(methoxymethyl or tetrahydropyranyl for example) with regeneration usinghydrochloric acid. As groups protecting carboxyl functions, there may bementioned esters (allyl or benzyl for example), oxazoles and2-alkyl-1,3-oxazolines. Other protecting groups which can be used aredescribed by GREEN T. W. et al., Protecting Groups in Organic Synthesis,second edition, 1991, John Wiley & Sons.

The compounds of formula (I) may be purified by the customary knownmethods, for example by crystallization, chromatography or extraction.

The enantiomers of the compounds of formula (I) may be obtained byresolution of the racemates for example by chromatography on a chiralcolumn according to PIRCKLE W. H. et al., Asymmetric synthesis, Vol. 1,Academic Press (1983) or by formation of salts or by synthesis fromchiral precursors. The diastereoisomers may be prepared according toknown conventional methods (crystallization, chromatography or fromchiral precursors).

The compounds of the formula (I) may be optionally converted to additionsalts with an inorganic or organic acid by the action of such an acid inan organic solvent such as an alcohol, a ketone, an ether or achlorinated solvent. These salts also form part of the invention.

As examples of pharmaceutically acceptable salts, the following saltsmay be mentioned: benzenesulfonate, hydrobromide, hydrochloride,citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate,maleate, methane sulfonate, methylene-bis-β-oxynaphtoate, nitrate,oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate,theophyllineacetate and p-toluenesulfonate.

The compounds of formula (I) exhibit advantageous pharmacologicalproperties. These compounds possess a high affinity for the cannabinoidreceptors and particularly those of the CBI type. They are CBI receptorantagonists and are therefore useful in the treatment and prevention ofdisorders affecting the central nervous system, the immune system, thecardiovascular or endocrine system, the respiratory system, thegastrointestinal apparatus and reproductive disorders (Hollister, Pharm.Rev.; 38 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991),Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology andNeurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992) ofbacterial, viral and parasitic infections.

Accordingly, these compounds may be used for the treatment or preventionof psychoses including schizophrenia, anxiety disorders, depression,epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders,cognitive disorders, cranial trauma, panic attacks, peripheralneuropathies, glaucomas, migraine, Parkinson's disease, Alzeimer'sdisease, Huntington's chorea, Raynaud's syndrome, tremor,obsessive-compulsive disorder, senile dementia, thymic disorders,Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancers,movement disorders induced by medicaments, dystonia, endotoxemic shocks,hemorrhagic shocks, hypotension, insomnia, immunological diseases,multiple sclerosis, vomiting, asthma, appetite disorders (bulimia,anorexia), obesity, memory disorders, in weaning from chronic treatmentsand alcohol or drug abuse (opiods, barbiturates, cannabis, cocaine,amphetamine, phencyclide, hallucinogens, benzodiazepines for example),as analgesics or potentiators of the analgesic activity of the narcoticand nonnarcotic drugs. They may also be used for the treatment orprevention of intestinal transit disorders, as antibacterial, antiviraland antiparasitic agents.

The affinity of the compounds of formula (I) for the cannabis receptorshas been determined according to the method described by KUSTER J. E.,STEVENSON J. I., WARS S. J., D'AMBRA T. E., HAYCOCK D. A. in J.Pharmacol. Exp. Ther., 264 1352-1363 (1993).

In this test, the IC₅₀ of the compounds of formula (I) is less than orequal to 100 nM.

Their antagonist activity has been shown by means of the model ofhypothermia induced by an agonist of the cannabis receptors (CO-55940)in mice, according to the method described by Pertwee R. G. inMarijuana, Harvey D. J. eds. 84 Oxford IRL Press, 263-277 (1985).

In this text the ED50 of the compounds of formula (I) is less than orequal to 50 mg/kg.

The preferred compounds of formula (I) are those for which R representsa chain (A) or (B) and R′ represents a hydrogen atom or a —COalkradical,

-   R₁ represents a methyl or ethyl radical,-   R₂ represents either an aromatic chosen from phenyl and naphthyl,    these aromatics being nonsubstituted or substituted with one or more    halogens, alkyl, alkoxy, hydroxyl, —COOR₅, trifluoromethyl,    trifluoromethyl-sulfanyl, trifluoromethoxy, —NR₆R₇, —CO—NH—NR₆R₇,    cyano, —CONHR₉, alkylsulfanyl, hydroxyalkyl, nitro, —CO—NR₁₆R₁₇,    —O-alkNR₁₂R₁₃ or alkylthioalkyl or a heteroaromatic chosen from    isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,    1,2,3,4-tetrahydroquinolyl and thienyl, these heteroaromatics being    unsubstituted or substituted with a halogen, alkyl, alkoxy, —COOR₅,    trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇,    —CO—NH—NR₆R₇, cyano, —CONHR₉, alkylsulfanyl, hydroxyalkyl, nitro or    alkylthioalkyl,-   R₃ and R₄, which are identical or different, represent either an    aromatic chosen from phenyl and naphthyl, these aromatics being    nonsubstituted or substituted with one or more halogens, alkyl,    alkoxy, trifluoromethyl, trifluoromethoxy, —CONR₁₀R₁₁, -alk-NR₆R₇,    hydroxyalkyl, formyl or —COOR₅, or a heteroaromatic chosen from    thiazolyl or thienyl rings, these heteroaromatics being    unsubstituted or substituted with a halogen, alkyl, alkoxy,    —CONR₁₀R₁₁, -alk-NR₆R₇, hydroxyalkyl or —COOR₅.-   R₅ is alkyl or phenyl which is optionally substituted with one or    more halogens,-   R₆ and R₇, which are identical or different, represent a hydrogen    atom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk    or hydroxyalkyl radical or alternatively R₆ and R₇ together form    with the nitrogen atom to which they are attached a 3- to    10-membered saturated or unsaturated mono- or bicyclic heterocycle    optionally containing another heteroatom chosen from oxygen, sulfur    and nitrogen and being optionally substituted with one or more    alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo,    hydroxyalkyl, alk-O-alk or —CO—NH₂ radicals,-   R₉ represents a hydrogen atom or an alkyl radical or an alkyl    radical substituted with dialkylamino, phenyl, cycloalkyl    (optionally substituted with —COOalk) or a 3- to 10-membered    saturated or unsaturated mono- or bicyclic heterocycle optionally    containing one or more heteroatoms chosen from oxygen, sulfur and    nitrogen and being optionally substituted with one ore more alkyl    radicals,-   R₁₀ and R₁₁, which are identical or different, represent a hydrogen    atom or an alkyl radical or alternatively R₁₀ and R₁₁ together form    with the nitrogen atom to which they are attached a 3- to    10-membered saturated mono- or bicyclic heterocycle optionally    containing another heteroatom chosen from oxygen, sulfur and    nitrogen and being optionally substituted with an alkyl radical,-   R₁₂ and R₁₃, which are identical or different, represent a hydrogen    atom or an alkyl or cycloalkyl radical or alternatively R₁₂ and R₁₃    together from with the nitrogen atom to which they are attached a 3-    to 10-membered saturated mono- or bicyclic heterocycle optionally    containing another heteroatom chosen from oxygen, sulfur and    nitrogen and being optionally substituted with an alkyl, —COalk,    —COOalk, —CO—NHalk, —CS—NHalk or —CO-alk-NR₁₄R₁₅ radical or a 3- to    10-membered saturated mono- or bicyclic heterocycle containing a    heteroatom chosen from oxygen, sulfur and nitrogen,-   R₁₄ and R₁₅, which are identical or different, represent a hydrogen    atom or an alkyl or —COOalk radical,-   R₁₆ and R₁₇ together form with the nitrogen atom to which they are    attached a 3- to 10-membered saturated mono- or bicyclic heterocycle    optionally containing another heteroatom chosen from oxygen, sulfur    and nitrogen,-   alk represents an alkyl or alkylene radical,-   their optical isomers and their salts with an inorganic or organic    acid.

The compounds of formula (I) which are particularly preferred are thosefor which

-   R represents a chain (A) or (B),-   R′ represents a hydrogen atom or a radical —COalk,-   R₁ represents a methyl or ethyl radical,-   R₂ represents either an aromatic chosen from-   naphthyl,-   phenyl-   phenyl substituted with one or more halogens, alkyl, alkoxy,    hydroxyl, —COOR₅ (in which R₅ represents an alkyl or phenyl radical    optionally substituted with several halogens) trifluoromethyl,    trifluoromethyl-sulfanyl, trifluoromethoxy, —NR₆R₇, (in which R₆ and    R₇, which are identical or different, represent a hydrogen atom or    an alkyl or —COOalk radical or alternatively R₆ and R₇ together form    with the nitrogen atom to which they are attached a heterocycle    chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl    substituted with one or more alkyl, —COalk, —COOalk, —CO—NHalk,    —CS—NHalk or —CO-alk-NR₁₄R₁₅ radicals, in which R₁₄ and R₁₅, which    are identical or different, represent a hydrogen atom or an alkyl    radical), —CO—NH—NR₆R₇(R₆ and R₇, which are identical or different,    represent a hydrogen atom or an alkyl radical or alternatively R₆    and R₇ together form with the nitrogen atom to which they are    attached a heterocycle chosen from piperidyl, piperazinyl or    piperazinyl substituted with one or more alkyl radicals), cyano,    —CONHR₉(in which R₉ represents a hydrogen atom or an alkyl radical    or an alkyl radical substituted with dialkylamino, phenyl,    cycloalkyl (optionally substituted with —COOalk) or a heterocycle    chosen from pyrrolidinyl (optionally substituted with alkyl),    tetrahydrofuryl, or morpholinyl), alkylsulfanyl, hydroxyalkyl,    nitro, —CO—NR₁₆R₁₇, (in which R₁₆ and R₁₇ together form with the    nitrogen atom to which they are attached a piperidyl ring),    —O-alkNR₁₂R₁₃ (in which R₁₂ and R₁₃ together from with the nitrogen    atom to which they are attached a morpholino ring) or    alkylthioalkyl, or a heteroaromatic chosen from-   isoquinolyl,-   pyridyl,-   quinolyl,-   1,2,3,4-tetrahydroisoquinolyl,-   1,2,3,4-tetrahydroquinolyl-   thienyl, or-   thienyl substituted with a —COOR₅ (in which R₅ represents an alkyl    radical) or —CONHR₉, (in which R₉ represents an alkyl radical),-   R₃ and R₄, which are identical or different, represent either an    aromatic chosen from-   phenyl or-   phenyl substituted with one or more halogen, alkyl, alkoxy,    trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, —COOR₅ (in    which R₅ is an alkyl radical), —CONR₁₀R₁₁ (in which R₁₀ and R₁₁,    which are identical or different, represent a hydrogen atom or an    alkyl radical), -alk-NR₆R₇ (in which R₆ and R₇, which are identical    or different, represent a hydrogen atom or an alkyl, cycloalkyl,    -alk-O-alk or hydroxyalkyl radical or alternatively R₆ and R₇    together form with the nitrogen atom to which they are attached a    heterocycle chosen from piperidyl (optionally substituted with alkyl    or oxo), pyrrolidinyl (optionally substituted with alkyl,    hydroxyalkyl, -alk-O-alk or —CO—NH₂), thiomorpholinyl, morpholinyl,    pyrrolyl, piperazinyl, optionally substituted with oxo, alkyl,    hydroxyalkyl, —COOR₅ (in which R₅ is an alkyl radical),-   or a heteroaromatic chosen from-   thiazolyl or-   thienyl,-   alk represents an alkyl or alkylene radical,-   their optical isomers and their salts with an inorganic or organic    acid.

Preferably, R₂ is a substituted phenyl radical, the latter ismonosubstituted and, in particular, at the 3-position or alternativelydisubstituted and, in particular at the 3,5, 2,5 or 2,3-positions.

Preferably, when R₃ is substituted phenyl radical, the latter ismonosubstituted and, in particular, at the 4-position or disubstitutedand, in particular, at the 2,4-positions.

Preferably, when R₄ is a substituted phenyl radical, the latter ismonosubstituted and, in particular, at the 4-position or disubstitutedand, in particular, at the 2,4-positions.

The following compounds may be mentioned among the preferred compounds:

-   1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-bromofluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidine,-   1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetidine,-   1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidine,-   1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3)-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,-   (R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,-   (S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,-   1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,-   1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis(trifluorophenyl)-phenyl]methylsulfonylmethylene}azetidine,-   (RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-{(4-chlorophenyl)[4-pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(RS)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(R)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)]-(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-methylsulfonyl)(3-pyrrolidinylphenyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethyl-phenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine,-   1-[bis(4-chlorophenyl)methyl]3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)-methylene]azetidine,-   1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   (S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   (RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamoyl]phenyl}(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)phenyl](methylsulfonyl)methylene}azetidine,-   1-[bis(thien-2yl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(p-tolyl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,-   1-[4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine,-   (RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   (S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine,-   (RS)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol,-   1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS)azetidin-3-ol,-   1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)methyl-(RS)azetidin-3-ol,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-morpholin-4-yl-propyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-piperidin-1-ylbenzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-isobutylbenzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide,-   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylaminoethyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic    acid N′-methylhydrazide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclohexylmethylbenzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclopropylmethylbenzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-methylbutyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-phenylpropyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide,-   3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide,-   4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylic    acid methyl ester,-   2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl]methyl]-azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanone,-   (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic    acid tert-butyl ester,-   1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone,-   (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic    acid tert-butyl ester,-   4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioic    acid N-methylamide,-   4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic    acid N-methylamide,-   4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic    acid methyl ester,-   1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine,-   1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-ethylpiperazine,-   4-acetyl    1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,-   1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone,-   1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,-   4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic    acid tert-butyl ester,-   1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidine,-   (RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)methanesulfonylmethylene]azetidin-1-yl}methyl)benzyl]morpholine,-   4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}butyl)morpholine,-   4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholine,-   their optical isomers and their esters.

Among these compounds, the following compounds are particularlypreferred:

-   1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,-   1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene(RS)]azetidin-3-ol,-   3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methyl-sulfonylmethyl(RS)]azetidine-   their optical isomers and their salts with an inorganic or organic    acid.

The following examples illustrate the invention without limiting it.

EXAMPLE 1

0.3 cm³ of methanesulfonyl chloride is added to a solution of 1 g or1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol in 10cm³ of pyridine, cooled to 5° C. The mixture is stirred for 2 hours at5° C. and then 1 g of 4-dimethylaminopyridine is added to 10 cm³ ofdichloromethane at 5° C. The solution is stirred for 15 hours at roomtemperature and then concentrated to a dryness under reduced pressure(2.7 kPa). The residue obtained is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm),eluting at a nitrogen pressure of 0.5 bar with dichloromethane andcollecting 80 cm³ fractions. Fractions 17 to 20 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). The residue iscrystallized from 10 cm³ of ethyl ether. 0.14 g of1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine is obtainedmelting at 210° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm (300 MHz):2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s,NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.),between 7.40 and 7.60 (9H, m, 9 CH arom.)].

1-Benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol may beobtained in the following manner: 6.25 cm³ of 1.6 N n-butyllithium insolution in hexane are added to a solution of 1.4 cm³ ofdiisopropylamine in 10 cm³ of tetrahydrofuran, under an argonatmosphere, cooled to 0° C., and then the mixture is cooled to −70° C. Amixture of 1.7 g of benzyl methyl sulfone in 30 cm³ of tetrahydrofuranare then added and the stirring is maintained for 45 minutes at −70° C.2.4 g of 1-benzhydrylazetidin-3-one are added and then the mixture isstirred for 20 minutes while allowing the mixture to return to roomtemperature. The reaction mixture is filtered and then concentrated todryness under reduced pressure (2.7 kPa). The residue is taken up in 50cm³ of ethyl acetate, 30 cm³ of water and 20 cm³ of normal hydrochloricacid. The precipitate is filtered, washed with 30 cm³ of distilledwater, drained and dried. 2 g of1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol areobtained melting at 260° C.

1-Benzhydrylazetidin-3-one may be prepared according to the proceduredescribed by KATRITZKY A. R. et al. in J. Heterocycl. Chem., 271 (1994).

EXAMPLE 2

On carrying out the operation according to the procedure of Example 1starting with 1.9 g of1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.52 cm³ of methanesulfonyl chloride and 1.7 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 17 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a dichloromethane and ethanol mixture (98.5/1.5by volume) as eluents and collecting 100 cm³ fractions, Fractions 5 and6 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from 2 cm³ of dichloromethaneand 20 cm³ of diisopropyl ether. 0.9 g of1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 180° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.35 (3H, s, PhCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂),4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.20 (5CH arom.), 7.30 (5H, t,J=7 Hz, 5CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.)].

1-Benzhydryl-3-[(3-methylphenyl)methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.8 g ofmethyl(3-methylbenzyl)sulfone and 3.6 g of 1-benzhydrylazetidin-3-one,2.6 g of a solid are obtained after purification on a silica gel column(particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogenpressure of 0.5 bar with a dichloromethane and ethanol mixture (98.5/1.5by volume) as eluent. The solid is taken up in 25 cm³ of diisopropylether. After filtration, draining and drying, 1.9 g of1-benzhydryl-3-[(3-methylphenyl)methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained melting at 170° C.

Methyl(3-methylbenzyl)sulfone may be prepared in the following manner:10.5 of oxone^(R) and then 2.6 g of methyl(3-methylbenzyl)sulfide and 30cm³ of ethanol are added, at room temperature, to a solution of 30 cm³of water, 30 cm³ of acetic acid and 15 cm³ of 36 N sulfuric acid. Themixture is stirred for 48 hours at room temperature and then taken up in100 cm³ of water and 100 cm³ of ethyl acetate. The organic phase iswashed with a saturated aqueous sodium bicarbonate solution, decantedoff, dried over magnesium sulfate and concentrated to dryness underreduced pressure (2.7 kPa). 2.8 g of methyl(3-methylbenzyl)sulfone areobtained in the form of a gum.

Methyl(3-methylbenzyl)sulfide may be prepared in the following manner:1.7 g of sodium methylthiolate are added, while the temperature is keptbelow 30° C., to a solution of 3.7 g of 3-methylbenzyl bromide in 25 cm³of dimethylformamide. The mixture is stirred for 2 hours at atemperature close to 20° C. and then taken up in 50 cm³ of ethylacetate. The organic phase is washed with 3 times 100 cm³ of water,dried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). 2.6 g of methyl)3-methyl-benzyl)sulfide are obtainedin the form of an oil.

EXAMPLE 3

0.3 cm³ of methanesulfonyl chloride is added to a solution of 3.3 g of1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)azetidin-3-olin 10 cm³ of pyridine, cooled to 5° C. The mixture is stirred for 2hours at 5° C. The solution is stirred for 15 hours at room temperatureand then concentrated to dryness under reduced pressure (2.7 kPa). Theresidue obtained is chromatographed on a silica gel column (particlesize 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting at a nitrogenpressure of 0.5 bar with dichloromethane and collecting 80 cm³fractions. Fractions 17 to 20 are combined and then concentrated todryness under reduced pressure (2.7 kPa). The solid obtained iscrystallized from 30 cm³ of acetonitrile. 0.14 g of1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 210° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.30 (3H, s, PhCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂),4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30(6H, t, J=7 Hz, 6CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].

1-Benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g ofmethyl(4-methylbenzyl)sulfone and 5.1 g of 1-benzhydrylazetidin-3-one, 3g of1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained melting at 226° C.

Methyl(4-methylbenzyl)sulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.5 g of methyl(4-methylbenzyl)sulfide and 12.3 g ofoxone^(R), 3.5 g of methyl(4-methylbenzyl)sulfone are obtained in theform of a solid.

Methyl(4-methylbenzyl)sulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 5.6 g of 4-methylbenzyl bromide and 2.3 g of sodiummethyltiolate, 4.7 g of methyl(4-methylbenzyl)sulfide are obtained inthe form of a solid.

EXAMPLE 4

0.7 cm³ of methanesulfonyl chloride and then 3.8 g of4-dimethylaminopyridine are added to a solution of 3.3 g of1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olin 50 cm³ of dichloromethane, at room temperature. The solution isstirred for 3 hours under reflux and then taken up in twice 50 cm³ ofwater. The organic phase is decanted off, dried and concentrated todryness under reduced pressure (2.7 kPa). The residue obtained ischromatographed on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm), eluting at a nitrogen pressure of 0.5 barwith dichloromethane and then with a dichloromethane and ethanol mixture(99/1 by volume mixture and collecting 100 cm³ fractions. Fractions 6 to17 are combined and then concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 50 cm³ of ethylether. 2.6 g of1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methylene]azetidine areobtained in the form of a foam [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 2.30 (3H, s, PhCH₃), 2.95 (3H, s, SCH₃), 3.50 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.70 (1H, s, NCH), between 7.10 and 7.35(10H, m, 10CH arom.), 7.45 (4H, m, 4CH arom.)].

1-Benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure Example 1 starting with 3.4 g ofmethyl(2-methylbenzyl)sulfone and 4.3 g of 1-benzhydrylazetidin-3-one,3.4 g of1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained melting at 218° C.

Methyl(2-methylbenzyl)sulfone may be prepared in the following manner:by carrying out the operation according to the procedure of Example 2starting with 4.5 g of methyl(2-methylbenzyl)sulfide and 16.2 g ofoxone^(R), 3.4 g of methyl(2-methylbenzyl)sulfone are obtained in theform of a solid.

Methyl(2-methylbenzyl)sulfide may be prepared in the following manner:by carrying out the operation according to the procedure of Example 2but starting with 5.6 g of 2-methylbenzyl bromide and 2.1 g of sodiummethylthiolate, 4.5 g of methyl(2-methylbenzyl)sulfide are obtained inthe form of a solid.

EXAMPLE 5

On carrying out the operation according to the procedure of Example 4but starting with 2.1 g of1-benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.55 cm³ of methanesulfonyl chloride and 2.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 12to 18 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 3 cm³ ofdichloromethane and 40 cm³ of ethyl ether. 1.1 g of1-benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 204° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.60 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (7H, m, 7CH arom.), 7.55 (1H, d, J=7 Hz, CH arom.)].

1-Benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(2-chlorobenzyl)methylsulfone and 4.6 g of 1-benzhydrylazetidin-3-one,the residue obtained is taken up in 50 cm³ of ethyl acetate, filteredand dried. 2.4 g of1-benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(2-Chlorobenzyl)methylsulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.4 g of (2-chlorobenzyl)methylsulfide and 12 g ofoxone^(R), 4 g of (2-chlorobenzyl)methylsulfone are obtained in the formof an oil which crystallizes.

(2-Chlorobenzyl)methylsulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2but starting with 4 g of 2-chlorobenzyl bromide and 1.5 g of sodiummethylthiolate, 3.4 g of (2-chlorobenzyl)methylsulfide are obtained inthe form of an oil.

EXAMPLE 6

On carrying out the operation according to the procedure of Example 4starting with 3 g of1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.79 cm³ of methanesulfonyl chloride and 3.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 2to 5 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 40 cm³ of ethylether. 1.7 g of1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 205° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (8H, m, 8CH arom.).

1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.1 g of(3-chlorobenzyl)methylsulfone and 3.4 g of 1-benzhydrylazetidin-3-one,3.4 g of1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(3-Chlorobenzyl)methylsulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.2 g of (3-chlorobenzyl)methylsulfide and 12 g ofoxone^(R), 3.2 g of (3-chlorobenzyl)methylsulfone are obtained in theform of a white solid.

(3-Chlorobenzyl)methylsulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 4 g of 3-chlorobenzyl bromide and 1.5 g of sodiummethylthiolate, 3.2 g of 3-chlorobenzylmethylsulfide are obtained in theform of an oil.

EXAMPLE 7

On carrying out the operation according to the procedure of Example 4starting with 3.3 g of1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.87 cm³ of methanesulfonyl chloride and 3.6 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 8to 12 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 3 cm³and 30 cm³ of ethyl ether. 0.5 g of1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 192° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), between 7.40 and 7.55 (8H, m, 8CH arom.).

1-Benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.8 g of(4-chlorobenzyl)methylsulfone and 3.24 g of 1-benzhydrylazetidin-3-one,3.4 g of1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid after crystallization from 80cm³.

(4-Chlorobenzyl)methylsulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.5 g of (4-chlorobenzyl)methylsulfide and 12.3 g ofoxone^(R), 3.5 g of (4-chlorobenzyl)methylsulfone are obtained in theform of a solid.

EXAMPLE 8

On carrying out the operation according to the procedure of Example 4starting with 3.1 g of1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.75 cm³ of methanesulfonyl chloride and 3.1 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 6to 10 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 2.3 cm³and 30 cm³ of ethyl ether. 0.8 g of1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidineis obtained melting at 204° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 2.95 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (1H, s, CH arom.)].

1-Benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(3,5-dichlorobenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one,3.2 g of1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(3,5 -Dichlorobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5.3 g of (3,5-dichlorobenzyl)methylsulfide and17 g of oxone^(R), 5 g of (3,5-dichlorobenzyl)methylsulfone are obtainedin the form of a white solid.

(3,5 -Dichlorobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5 g of 3,5-dichlorobenzyl chloride and 2 g ofsodium methylthiolate, 5.3 g of (3,5-dichlorobenzyl)methylsulfide areobtained in the form of an oil.

EXAMPLE 9

On carrying out the operation according to the procedure of Example 4starting with 5 g of1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.2 cm³ of methanesulfonyl chloride and 3.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with amixture of cyclohexane and ethyl acetate (70/30 by volume) as eluent andcollecting 35 cm³ fractions. Fractions 30 to 55 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 50 cm³ of ethyl ether. 1.5 g of1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 170° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), between 7.35 and 7.50 (5H, m, 5CH arom.), 7.65 (2H,s, 2CH arom.)].

1-Benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(3,4-dichlorobenzyl)methylsulfone and 4.3 g of1-benzhydrylazetidin-3-one, 5 g of1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(3,4-Dichlorobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4.3 g of (3,4-dichlorobenzyl)methylsulfide and13 g of oxone^(R), 4.7 g of (3,4-dichlorobenzyl)methylsulfone areobtained in the form of a white solid.

(3,4-Dichlorobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 2.8 cm³ of 3,4-dichlorobenzyl chloride and 1.5 gof sodium methylthiolate, 4.3 g of (3,4-dichlorobenzyl)methylsulfide areobtained in the form of an oil.

EXAMPLE 10

On carrying out the operation according to the procedure of Example 4starting with 1.8 g of1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.4 cm³ of methanesulfonyl chloride and 1.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 8to 14 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 2 cm³ ofdichloromethane and 30 cm³ of ethyl ether. 1.2 g of1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 202° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.70 (2H, m, NCH₂), 4.25 (2H, m,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), between 7.55 and7.70 (3H, m, 3CH arom.)].

1-Benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 1.2 g of(2,5-dichlorobenzyl)methylsulfone and 1.2 g of1-benzhydrylazetidin-3-one, 1.8 g of1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(2,5-Dichlorobenzyl)methylsulfone may be prepared in the followingmanner: 1.9 g of sodium methanesulfinate are added, at room temperature,to a solution of 2.7 g of 2,5-dichlorobenzyl chloride in 30 cm³ ofethanol. The mixture is heated under reflux for 5 hours, cooled to roomtemperature and then taken up in 50 cm³ of water and 50 cm³ of ethylacetate. The organic phase is decanted off, washed with 20 cm³ of asaturated aqueous sodium chloride solution, dried over magnesium sulfateand concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of(2,5-dichlorobenzyl)methylsulfone are obtained in the form of a whitesolid.

EXAMPLE 11

On carrying out the operation according to the procedure of Example 4starting with 9.1 g of1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,2.2 cm³ of methanesulfonyl chloride and 7 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 40 cm³ fractions. Fractions 27 to 39 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 20 cm³ of ethyl ether. 1.5 g of1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 165° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.65 (2H, m, NCH₂), 4.25 (2H, m,NCH₂), 4.75 (1.75H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H,t, J=7 Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.80 (1H, s, CH arom.)].

1-Benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4.8 g of(2,4-dichlorobenzyl)methylsulfone and 4.7 g of1-benzhydrylazetidin-3-one, 9.1 g of1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a brown foam.

(2,4-Dichlorobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4 g of (2,4-dichlorobenzyl)methylsulfide and 13g of oxone^(R), 4.8 g of (2,4-dichlorobenzyl)methylsulfone are obtainedin the form of a white solid melting at 111° C.

(2,4-Dichlorobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 2.8 cm³ of 2,4-dichlorobenzyl chloride and 1.5 gof sodium methylthiolate, 4 g of (2,4-dichlorobenzyl)methylsulfide areobtained in the form of an oil.

EXAMPLE 12

On carrying out the operation according to the procedure of Example 4starting with 3 g of1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.1 g of methanesulfonyl chloride and 3 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at anitrogen pressure of 0.5 bar with a mixture of dichloromethane andethanol (98/2 by volume) as eluent and collecting 100 cm³ fractions.Fractions 10 to 20 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from 40cm³ of ethyl ether. 1.6 g of1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 201° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.60 (2H, m, NCH₂), 4.20 (2H, m,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (1H, dd, J=8 and 2 Hz,CH arom.)].

1-Benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.6 g of(2,3-dichlorobenzyl)methylsulfone and 3.6 g of1-benzhydrylazetidin-3-one, 5.4 g of1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(2,3-Dichlorobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 10 starting with 3 g of 2,3-dichlorobenzyl chloride and 2.4 g ofsodium methanesulfinate, 3.6 g of (2,3-dichlorobenzyl)methylsulfonateare obtained in the form of a white solid.

EXAMPLE 13

On carrying out the operation according to the procedure of Example 4starting with 2.5 g of1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.72 cm³ of methanesulfonyl chloride and 2.9 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent, collecting 100 cm³ fractions. Fractions 2 to6 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from 40 cm³ of ethyl ether. 1.5g of 1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 210° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, m, NCH₂), 4.20 (2H, s,NCH₂), 4.70 (1H, s, NCH), between 7.10 and 7.30 (9H, m, 9CH arom.), 7.45(5H, m, 5CH arom.)].

1-Benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.6 g of3-fluorobenzyl methyl sulfone and 3.3 g of 1-benzhydrylazetidin-3-one,2.9 g of1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid melting at 200° C.

(3-Fluorobenzyl) methyl sulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.1 g of 3-fluorobenzyl methyl sulfide and 13 g ofoxone^(R), 2.7 g of 3-fluorobenzyl methyl sulfone are obtained in theform of a white solid.

(3-Fluorobenzyl) methyl sulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 2.6 cm³ of 3-fluorobenzyl bromide and 1.6 g of sodiummethylthiolate, 3.1 g of 3-fluorobenzyl methyl sulfide are obtained inthe form of an oil.

EXAMPLE 14

On carrying out the operation according to the procedure of Example 4starting with 4.3 g of1-benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.2 cm³ of methanesulfonyl chloride and 3.7 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 30 cm³ fractions. Fractions 28to 58 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 100 cm³ of ethylether. 2.3 g of1-benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 188° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.65 (2H, m, NCH₂), 4.20 (2H, m, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (6H, m, 6CHarom.), 7.50 (6H, m, 6CH arom.)].

1-Benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.4 g of2-fluorobenzyl methyl sulfone and 4.2 g of 1-benzhydrylazetidin-3-one,4.3 g of1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(2-Fluorobenzyl) methyl sulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3 g of 2-fluorobenzyl methyl sulfide and 13 g ofoxone^(R), 3.6 g of 3-fluorobenzyl methyl sulfone are obtained in theform of a white solid.

(2-Fluorobenzyl) methyl sulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 2.4 cm³ of 2-fluorobenzyl bromide and 1.5 g of sodiummethylthiolate, 3 g of 2-fluorobenzyl methyl sulfide are obtained in theform of an oil.

EXAMPLE 15

On carrying out the operation according to the procedure of Example 4starting with 1 g of1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 0.9 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 30 cm³ fractions. Fractions 20to 35 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 50 cm³ of ethylether. 0.4 g of1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 186° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, m, NCH₂), 4.20 (2H, m, NCH₂),4.75 (1H, s, NCH), between 7.15 and 7.35 (8H, m, 8CH arom.), 7.45 (6H,m, 6CH arom.)].

1-Benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.8 g of4-fluorobenzyl methyl sulfone and 3.6 g of 1-benzhydrylazetidin-3-one, 1g of1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(4-Fluorobenzyl) methyl sulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3 g of 4-fluorobenzyl methyl sulfide and 13 g ofoxone^(R), 3 g of 4-fluorobenzyl methyl sulfone are obtained in the formof a white solid melting at 110° C.

(4-Fluorobenzyl) methyl sulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 2.5 cm³ of 4-fluorobenzyl chloride and 1.5 g of sodiummethylthiolate, 3 g of 4-fluorobenzyl methyl sulfide are obtained in theform of an oil.

EXAMPLE 15

On carrying out the operation according to the procedure of Example 4starting with 3.8 g of1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1 cm³ of methanesulfonyl chloride and 4.2 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 100 cm³ fractions. Fractions 5 to 10 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 30 cm³ of ethyl ether. 0.8 g of1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 172° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, m, NCH₂), 4.20 (2H, m,NCH₂), 4.75 (1H, s, NCH), between 7.10 and 7.40 (9H, m, 9CH arom.), 7.50(4H, d, J=7 Hz, 4CH arom.)].

1-Benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.2 g of3,5-difluorobenzyl methyl sulfone and 3.7 g of1-benzhydrylazetidin-3-one, 3.9 g of1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(3,5-Difluorobenzyl) methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4.2 g of 3,5-difluorobenzyl methyl sulfide and16 g of oxone^(R), 3.3 g of 3,5-difluorobenzyl methyl sulfone areobtained in the form of a white solid.

(3,5-Difluorobenzyl) methyl sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5 g of 3,5-difluorobenzyl bromide and 1.5 g ofsodium methylthiolate, 4.9 g of 3,5-difluorobenzyl methyl sulfide areobtained in the form of an oil.

EXAMPLE 17

On carrying out the operation according to the procedure of Example 4starting with 5.2 g of1-benzhydryl-3-[(2,3-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,2.3 cm³ of methanesulfonyl chloride and 7.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and methanol (98/2 by volume) as eluent andcollecting 50 cm³ fractions. Fractions 65 to 87 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 100 cm³ of ethyl ether. 2.5 g of1-benzhydryl-3-[(2,3-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 208° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (400 MHz): 3.05 (3H, s, SCH₃), 3.70 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.55 (13H, m, 13CH arom.)].

1-Benzhydryl-3-[(2,3-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(2,3-difluorobenzyl) methyl sulfone and 4.8 g of1-benzhydrylazetidin-3-one, 5.5 g of1-benzhydryl-3-[(2,3-difluorophenyl)(methyl-sulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(2,3-Difluorobenzyl) methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 10 starting with 4.1 g of 2,3-difluorobenzyl bromide and 4.1 gof sodium methanesulfinate, 4 g of (2,3-difluorobenzyl) methyl sulfoneare obtained in the form of a white solid.

EXAMPLE 18

On carrying out the operation according to the procedure of Example 4starting with 5.2 g of1-benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,2.3 cm³ of methanesulfonyl chloride and 7.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and methanol (98/2 by volume) as eluent andcollecting 50 cm³ fractions. Fractions 73 to 90 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 75 cm³ of ethyl ether. 2.6 g of1-benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 176° C.

1-Benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(2,5-difluorobenzyl) methyl sulfone and 4.8 g of1-benzhydrylazetidin-3-one, 5.9 g of1-benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a cream-colored solid.

(2,5-Difluorobenzyl) methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 10 starting with 4.1 g of 2,5-difluorobenzyl bromide and 4.1 gof sodium methanesulfinate, 4.8 g of (2,5-difluorobenzyl) methyl sulfoneare obtained in the form of a white solid.

(2-Fluorobenzyl) methyl sulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 2.4 cm³ of 2-fluorobenzyl bromide and 1.5 g of sodiummethylthiolate, 3 g of 2-fluorobenzyl methyl sulfide are obtained in theform of an oil.

EXAMPLE 19

On carrying out the operation according to the procedure of Example 4starting with 7.7 g of1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.8 cm³ of methanesulfonyl chloride and 5.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a dichloromethane and ethanol mixture (99.5/0.5by volume) as eluents and collecting 100 cm³ fractions. Fractions 17 to28 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from 5 cm³ of dichloromethaneand 50 cm³ of ethyl ether. 3.5 g of1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 200° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.25 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), between 7.35 and 7.55 (6H, m, 6CH arom.), 7.65 (2H, m, 2CHarom.)].

1-Benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 8 g of3-bromobenzyl methyl sulfone and 7.6 g of 1-benzhydrylazetidin-3-one, 8g of1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

3-Bromobenzyl methyl sulfone may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 9 g of 3-bromobenzyl methyl sulfide and 27 g of oxone^(R),8.2 g of 3-bromobenzyl methyl sulfone are obtained in the form of awhite solid.

3-Bromobenzyl methyl sulfide may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 10 g of 3-bromobenzyl bromide and 3.1 g of sodiummethylthiolate, 9 g of 3-bromobenzyl methyl sulfide are obtained in theform of an oil.

EXAMPLE 20

On carrying out the operation according to the procedure of Example 4starting with 1.5 g of1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 1.4 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a mixture of dichloromethane and ethanol(99.7/0.3 by volume) as eluents and collecting 100 cm³ fractions.Fractions 16 to 24 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from amixture of 1.5 cm³ of dichloromethane and 25 cm³ of ethyl ether. 0.5 gof 1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 198° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), between 7.10 and 7.30 (7H, m, 7CH arom.), 7.45 (5H,m, 5CH arom.), 7.80 (2H, m, 2CH arom.)].

1-Benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.7 g of3-iodobenzyl methyl sulfone and 3 g of 1-benzhydrylazetidin-3-one, 1.5 gof1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

3-Iodobenzyl methyl sulfone may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 3.6 g of 3-iodobenzyl methyl sulfide and 10.3 g ofoxone^(R), 3.7 g of 3-iodobenzyl methyl sulfone are obtained in the formof a white solid.

3-Iodobenzyl) methyl sulfide may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 5 cm³ of 3-iodobenzyl bromide and 1.3 g of sodiummethylthiolate, 4 g of 3-iodobenzyl methyl sulfide are obtained in theform of an oil.

EXAMPLE 21

On carrying out the operation according to the procedure of Example 4starting with 2.4 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-ol,0.6 cm³ of methanesulfonyl chloride and 2.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a mixture of dichloromethane and ethanol(99.7/0.3 by volume) as eluents and collecting 100 cm³ fractions.Fractions 12 to 25 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from amixture of 2 cm³ of dichloromethane and 30 cm³ of ethyl ether. 0.7 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidineis obtained melting at 162° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.40 (6H, m, 6CH arom.),between 7.45 and 7.55 (7H, m, 7CH arom.), 7.60 (1H, t, J=7 Hz, CHarom.)].

1-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.4 g ofmethyl(3-trifluoromethoxybenzyl)sulfone and 2.2 g of1-benzhydrylazetidin-3-one, 2.4 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

Methyl(3-fluoromethoxybenzyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 2.6 g of methyl(3-trifluoromethoxybenzyl)sulfideand 7.2 g of oxone^(R), 2.4 g ofmethyl(3-trifluoromethyoxybenzyl)sulfone are obtained in the form of awhite solid.

Methyl(3-trifluoromethoxybenzyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3 g of 3-trifluoromethoxybenzyl bromide and 1 gof sodium methylthiolate, 3.3 g ofmethyl(3-trifluoromethoxybenzyl)sulfide are obtained in the form of anoil.

EXAMPLE 22

On carrying out the operation according to the procedure of Example 4starting with 4.1 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS)]azetidin-3-ol,1 cm³ of methanesulfonyl chloride and 4.2 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting100 cm³ fractions. Fractions 10 to 14 are combined and concentrated todryness under reduced pressure (2.7 kPa). The solid obtained iscrystallized from a mixture of 2 cm³ of dichloromethane and 30 cm³ ofethyl ether. 1.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetidineare obtained melting at 178° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.15 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), between 7.60 and7.80 (4H, m, 4CH arom.)].

1-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.4 g ofmethyl(3-trifluoromethylbenzyl)sulfone and 3.4 g of1-benzhydrylazetidin-3-one, 4.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

Methyl(3-trifluoromethylbenzyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.3 g of methyl(3-trifluoromethylbenzyl)sulfideand 10 g of oxone^(R), 3.4 g of methyl(3-trifluoromethylbenzyl)sulfoneare obtained in the form of a white solid.

Methyl(3-trifluoromethylbenzyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.9 g of 3-trifluoromethylbenzyl bromide and 1.4g of sodium methylthiolate, 3.3 g ofmethyl(3-trifluoromethylbenzyl)sulfide are obtained in the form of anoil.

EXAMPLE 23

On carrying out the operation according to the procedure of Example 4starting with 2.7 g of1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.6 cm³ of methanesulfonyl chloride and 2.4 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent, collecting 100 cm³ fractions. Fractions 7 to12 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from 10 cm³ of ethyl ether. 1 gof1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidineare obtained melting at 192° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.15 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.15 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 8.05 (2H, s, 2CHarom.), 8.15 (1H, s, CH arom.)].

1-Benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.1 g ofmethyl[3,5-bis(trifluoromethyl)benzyl]sulfone and 2.4 g of1-benzhydrylazetidin-3-one, 2.8 g of1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidin-3-olare obtained in the form of a white solid.

Methyl[3,5-bis(trifluoromethyl)benzylsulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 10 starting with 3 g of3,5-bis(trifluoromethyl)benzyl chloride and 2 g of sodiummethanesulfinate, 3.1 g of methyl[3,5-bis(trifluoromethyl)benzyl]sulfoneare obtained in the form of a white solid melting at 132° C.

EXAMPLE 24

On carrying out the operation according to the procedure of Example 4starting with 10.7 g of1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,2.2 cm³ of methanesulfonyl chloride and 7 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 35 cm³ fractions. Fractions 40 to 58 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 50 cm³ of ethyl ether. 1.5 g of1-benzhydryl-3-[3,5-dibromophenyl)(methylsulfonyl)methylene}azetidineare obtained melting at 209° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.88 (2H, s, NCH₂), 4.22 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.33 (4H, t,J=7 Hz, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 7.68 (2H, s, 2CHarom.), 7.95 (1H, s, CH arom.)].

1-Benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 6.2 g of(3,5-dibromobenzyl)methylsulfone and 4.5 g of1-benzhydrylazetidin-3-one, 10.7 g of1-benzhydryl-3-[3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

(3,5-Dibromobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5.8 g of (3,5-dibromobenzyl)methylsulfide and 13g of oxone^(R), 6.2 g of (3,5-dibromobenzyl)methylsulfone are obtainedin the form of a white solid.

(3,5-Dibromobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 6.6 g of 3,5-dibromobenzyl bromide and 1.5 g ofsodium methylthiolate, 5.8 g of (3,5-dibromobenzyl)methylsulfide areobtained in the form of an oil.

EXAMPLE 25

On carrying out the operation according to the procedure of Example 4starting with 4.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl-(RS)]azetidin-3-ol,1.1 cm³ of methanesulfonyl chloride and 2.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with amixture of cyclohexane and ethyl acetate (50/50 dichloromethane aseluents, collecting 400 cm³ fractions. Fractions 17 to 33 are combinedand concentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 15 cm³ of ethyl acetate. 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methylene]azetidine isobtained melting at 184° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.25 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.75 (1H, t, J=7 Hz, CHarom.), 7.85 (1H, d, J=7 Hz, CH arom.), 8.25 (2H, m, 2CH arom.)].

1-Benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.9 g ofmethyl(3-nitrobenzyl)sulfone and 4.2 g of 1-benzhydrylazetidin-3-one,4.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

Methyl(3-nitrobenzyl)sulfone may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 18.1 g of methyl(3-nitrobenzyl)sulfide and 68 g ofoxone^(R), 13.9 g of methyl(3-nitrobenzyl)sulfone are obtained in theform of a foam.

Methyl(3-nitrobenzyl)sulfide may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 17.2 g of 3-nitrobenzyl chloride and 7.7 g of sodiummethylthiolate, 18.2 g of methyl(3-nitrobenzyl)sulfide are obtained inthe form of an oil.

EXAMPLE 26

A mixture of 0.34 g of1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methylene]azetidine, 16cm³ of 1 N hydrochloric acid in 8 cm³ of ethanol and 16 cm³ oftetrahydrofuran is heated under reflux. 0.17 g of iron powder is addedand the reflux is maintained for 3 hours. The mixture is then cooled toroom temperature and the insoluble matter is filtered off. The solutionis taken up in 10 cm³ of 1 N sodium hydroxide and 50 cm³ of a saturatedaqueous sodium chloride solution. The aqueous phase is extracted with 3times 40 cm³ of dichloromethane, the extracts are combined, dried oversodium sulfate and concentrated to dryness under reduced pressure (2.7kPa). The residue is purified on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) aseluent, collecting 20 cm³ fractions. Fractions 13 to 31 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 15 cm³ of ethyl ether. 0.17 g of3-[(3-aminophenyl)(methylsulfonyl)methylene]-1-benzhydrylazetidine isobtained melting at 197° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(250 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.25 (2H, s, NCH₂),4.75 (1H, s, NCH), 5.25 (2H, s, NH₂), 6.55 (3H, m, 3CH arom.), 7.05 (1H,t, J=7 Hz, CH arom.), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].

EXAMPLE 27

On carrying out the operation according to the procedure of Example 4starting with 1.2 g of1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 1.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and then a mixture of dichloromethane and ethyl acetate(99.5/0.5 by volume) as eluents and collecting 100 cm³ fractions.Fraction 18 is concentrated to dryness under reduced pressure (2.7 kPa).The solid obtained is precipitated in 5 cm³ of ethyl ether. 0.13 g of1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)(methylene]azetidineis obtained in the form of a foamy solid [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30(4H, t, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.60 (1H,t, J=7 Hz, CH arom.), 7.70 (1H, d, J=7 Hz, CH arom.), 8.00 (2H, m, 2CHarom.)].

1-Benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3 g of(3-methoxycarbonylbenzyl)methylsulfone and 3.6 g of1-benzhydrylazetidin-3-one, 1.2 g of1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam after purification by chromatographyon a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm,height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane andthen a dichloromethane and ethanol mixture (99/1 by volume as eluents.

(3-Methoxycarbonylbenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4.3 g of (3-methoxycarbonylbenzyl)methylsulfideand 13.4 g of oxone^(R), 3.4 g of (3-methoxycarbonylbenzyl)methylsulfoneare obtained in the form of a white solid.

(3-Methoxycarbonylbenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5 g of 3-methoxycarbonylbenzyl bromide and 1.7 gof sodium methylthiolate, 4.3 g of(3-methoxycarbonylbenzyl)methylsulfide are obtained in the form of anoil.

EXAMPLE 28

On carrying out the operation according to the procedure of Example 4starting with 6.2 g of1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.6 cm³ of methanesulfonyl chloride and 6.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and then a dichloromethane and ethyl acetate mixture(99.5/0.5 by volume) as eluents and collecting 250 cm³ fractions.Fractions 10 to 15 are concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 5 cm³ ofdichloromethane and 70 cm³ of ethyl ether. 2.9 g of1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)(methylene]azetidine areobtained melting at 152° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.65 (1H, t, J=7 Hz, CHarom.), 7.75 (1H, d, J=7 Hz, CH arom.), 7.90 (2H, m, 2CH arom.)].

1-Benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.9 g of(3-cyanobenzyl)methylsulfone and 4.7 g of 1-benzhydrylazetidin-3-one,6.2 g of1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(3-Cyanobenzyl)methylsulfone may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 6.7 g of (3-cyanobenzyl)methylsulfide and 27.6 g ofoxone^(R), 3.9 g of (3-cyanobenzyl)methylsulfone are obtained in theform of a white solid.

(3-Cyanobenzyl)methylsulfide may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 2starting with 8 g of 3-cyanobenzyl bromide and 3.1 g of sodiummethylthiolate, 6.8 g of (3-cyanobenzyl)methylsulfide are obtained inthe form of an oil.

EXAMPLE 29

A mixture of 3 g of1-benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride, 1.3 g of pentafluorophenol, 1.4 g of1(3-dimethylaminopropyl)-3-ethylcarbodiimide in 30 cm³ ofdimethylformamide is stirred at room temperature for 15 hours. Themixture is taken up in 100 cm³ of water and 100 cm³ of a saturatedaqueous sodium chloride solution and 50 cm³ of ethyl acetate. Theorganic phase is decanted off, dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). The residue ispurified by chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5bar with dichloromethane and then a dichloromethane and methanol mixture(99.4/0.6 by volume) as eluents and collecting 100 cm³ fractions.Fractions 13 to 16 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from 10cm³ of ethyl ether. 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(3-pentafluorophenoxycarbonylphenyl)methylene]azetidineis obtained melting at 182° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (400 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.70 (1H, t, J=7Hz, CH arom.), 8.20 (2H, m, 2CH arom.)].

1-Benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride may be prepared in the following manner: a mixture of 10 gof 1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine in40 cm³ of acetic acid and 40 cm³ of concentrated hydrochloric acid(d=1.18) is heated at 45° C. for 7 days. The reaction medium is cooledon an ice-cold water bath and the precipitate formed is filtered onsintered glass. The solid is washed with 20 cm³ of a mixture of aceticacid and concentrated hydrochloric acid (50-50 by volume) and then with3 times 20 cm³ of water and finally with 20 cm³ of ethanol. The whitesolid obtained is under reduced pressure (2.7 kPa) at 45° C. and 2.5 gof 1-benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride are obtained in the form of a white solid.

EXAMPLE 30

A solution of 0.65 g of1-benzhydryl-3-[(methylsulfonyl)(3-pentafluorophenoxycarbonylphenyl)methylene]azetidinein 25 cm³ of 6.2 N ammoniacal ethanol is stirred for 4 hours at roomtemperature. The mixture is concentrated to dryness under reducedpressure (2.7 kPa) and then the residue is purified by chromatography ona silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height30 cm) at a nitrogen pressure of 0.5 bar with a dichloromethane andethanol mixture (98/2 by volume) and then a dichloromethane and ethanolmixture (98/2 by volume) as eluents and collecting 60 cm³ fractions.Fractions 18 to 30 are combined and concentrated to dryness underreduced pressure (2.7 kPa). 0.2 g of1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidineis obtained melting at 140° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.25 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), between 7.45 and 7.65 (7H, m, 6CH arom. and 2CONH₂), 7.95 (2H, m, 2CH arom.), 8.10 (1H, s, 2 CONH₂).

EXAMPLE 31

On carrying out the operation according to the procedure of Example 4starting with 4.6 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.2 cm³ of methanesulfonyl chloride and 3.8 g of4-dimethylaminopyridine, 2.6 of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine areobtained, after recrystallization from 150 cm³ of acetonitrile, meltingat 179° C. 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and then a dichloromethane and ethyl acetate mixture(99.5/0.5 by volume) as eluents and collecting 250 cm³ fractions.Fractions 10 to 15 are concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 5 cm³ ofdichloromethane and 70 cm³ of ethyl ether. 2.9 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)(methylene]azetidineare obtained melting at 152° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 2.95 (3H, s, SCH₃), 3.75 (3H, s, OCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.00 (3H, m, 3 CH arom.),between 7.20 and 7.12 (11H, m, 10H phenyls and 1 CH arom.)].

1-Benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.4 g of(3-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one,4.6 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(3-Methoxybenzyl)methylsulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.4 g of (3-methoxybenzyl)methylsulfide and 13 g ofoxone^(R), 4 g of (3-methoxybenzyl)methylsulfone are obtained in theform of a white solid melting at 71° C.

(3-Methoxybenzyl)methylsulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.1 g of 3-methoxybenzyl bromide and 1.5 g of sodiummethylthiolate, 3.4 g of (3-methoxybenzyl)methylsulfide are obtained inthe form of an oil.

EXAMPLE 32

10 cm³ of a 1 M solution of boron tetrabromide in dichloromethane areadded, with stirring, to a solution of 1.3 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine in100 cm³ of dichloromethane. The stirring is maintained for 16 hours atroom temperature. The reaction medium is taken up in 100 cm³ of water,dried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). The residue is precipitated in 150 cm³ of isopropylether and then dissolved in 50 cm³ of dichloromethane. The organic phaseis washed with 3 times 30 cm³ of a saturated aqueous solution of sodiumbicarbonate, decanted off, dried over magnesium sulfate and concentratedto dryness under reduced pressure (2.7 kPa). The residue is precipitatedin 80 cm³ of ethyl ether. 0.36 g of1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine isobtained from a solid melting at 248° C. [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.75 (1H, s, NCH), 6.85 (3H, m, 3 CH arom.), 7.25 (3H, m,3 CH arom.), 7.35 (4H, t, J=7 Hz, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CHarom.), 9.50 (1H, s, OH)].

EXAMPLE 33

On carrying out the operation according to the procedure of Example 32starting with 1.4 g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine, 10cm³ of a 1 M boron tribromide solution and 100 cm³ of dichloromethane,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3.5 cm, height 24 cm) at anitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethylacetate (50/50 by volume) as eluents and collecting 25 cm³ fractions.Fractions 21 to 37 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from amixture of 30 cm³ of ethyl ether. 0.6 g of1-benzhydryl-3-[(4-hydroxyphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 211° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.90 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 6.80 (2H, d, J=7 Hz, 2CH arom.), between 7.10 and7.35 (8H, m, 8CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 9.80 (1H, s,OH)].

1-Benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine maybe obtained in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 3.5 g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.9 cm³ of methanesulfonyl chloride and 2.9 g of4-dimethylaminopyridine, the residue obtained is purified byrecrystallization from 100 cm³ of acetonitrile, 1 g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 181° C.

1-Benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.5 g of4-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one, 3.6g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

(4-Methoxybenzyl)methylsulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.4 g of (4-methoxybenzyl)methylsulfide and 13 g ofozone^(R), 3.5 g of (3-methoxybenzyl)methylsulfone are obtained in theform of a white solid melting at 113° C.

(4-Methoxybenzyl)methylsulfide may be prepared in the following manner:on carrying out the operation according to the procedure of Example 2starting with 3.1 g of 4-methoxybenzyl chloride and 1.5 g of sodiummethylthiolate, 3.4 g of (4-methoxybenzyl)methylsulfide are obtained inthe form of an oil.

EXAMPLE 34

On carrying out the operation according to the procedure of Example 32starting with 1.4 g of1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine, 10cm³ of a 1 M boron tribromide and 100 cm³ of dichloromethane, theresidue obtained is purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogenpressure of 0.5 bar with dichloromethane as eluent and collecting 40 cm³fractions. Fractions 15 to 34 are combined and concentrated to drynessunder reduced pressure (2.7 kPa). The solid obtained is crystallizedfrom 40 cm³ of ethyl ether. 0.7 g of1-benzhydryl-3-[(2-hydroxyphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 196° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.60 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 6.85 (1H, t, J=7 Hz, CH arom.), 6.90 (1H, d, J=7 Hz,CH arom.), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.),7.48 (4H, d, J=7 Hz, 4CH arom.), 9.90 (1H, s, OH)].

1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine maybe obtained in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 4.2 g of1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.1 cm³ of methanesulfonyl chloride and 3.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethyl acetate (50/50 by volume) aseluents and collecting 40 cm³ fractions. Fractions 23 to 54 are combinedand concentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 40 cm³ of ethyl ether. 1.9 g of1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 204° C.

1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of2-methoxybenzyl)methylsulfone and 4.5 g of 1-benzhydrylazetidin-3-one,4.3 g of1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a brown foam.

(2-Methoxybenzyl)methylsulfone may be prepared in the following manner:on carrying out the operation according to the procedure of Example 10starting with 3.1 g of (2-methoxybenzyl)chloride and 4.1 g of sodiummethanesulfinate, 4 g of (2-methoxybenzyl)methylsulfone are obtained inthe form of a white solid.

EXAMPLE 35

On carrying out the operation according to the procedure of Example 4starting with 2.1 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]azetidin-3-ol,0.5 cm³ of methanesulfonyl chloride and 2.2 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 6to 10 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 20 cm³ of ethylether. 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methylene]azetidine isobtained melting at 178° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.35 (4H, t, J=7 Hz, CHarom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.52 (3H, m, 3CH arom.), 7.90(4H, m, 4CH arom.)].

1-Benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.5 g ofmethyl(naphth-2-ylmethyl)sulfone and 3.8 g of1-benzhydrylazetidin-3-one, 2.2 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]-azetidin-3-olare obtained in the form of a white solid melting at 196° C.

Methyl(naphth-2-ylmethyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4.2 g of methyl(naphth-2-ylmethyl)sulfide and13.7 g of oxone^(R), 3.6 g of methyl(naphth-2-ylmethyl)sulfone areobtained in the form of a cream-colored solid.

Methyl(naphth-2-ylmethyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5 g of (2-bromomethyl)naphthalene and 1.8 g ofsodium methylthiolate, 4.2 g of methyl(naphth-2-ylmethyl)sulfide areobtained in the form of an oil.

EXAMPLE 36

On carrying out the operation according to the procedure of Example 4starting with 4.3 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]azetidin-3-ol,1.1 cm³ of methanesulfonyl chloride and 4.6 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 6to 14 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 30 cm³ of ethylether. 2.5 g of 1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methylene]azetidine are obtained melting at 196° C. [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 3.00 (3H, s, SCH₃), 3.35 and 3.50 (1H each,dd, J=16 and 3 Hz, NCH₂), 4.35 (2H, s, NCH₂), 4.75 (1H, s, NCH), between7.10 and 7.70 (14H, m, 14CH arom.), 8.00 (3H, m, 3CH arom.)].

1-Benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4.1 g ofmethyl(naphth-1-ylmethyl)sulfone and 4.4 g of1-benzhydrylazetidin-3-one, 4.3 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]-azetidin-3-olare obtained in the form of a solid.

Methyl(naphth-1-ylmethyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4.3 g of methyl(naphth-1-ylmethyl)sulfide and13.9 g of oxone^(R), 4.1 g of methyl(naphth-1-ylmethyl)sulfone areobtained in the form of a white solid.

Methyl(naphth-1-ylmethyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4 g of 1-chloromethylnaphthalene chloride and1.8 g of sodium methylthiolate, 4.5 g ofmethyl(naphth-1-ylmethyl)sulfide are obtained in the form of an oil.

EXAMPLE 37

On carrying out the operation according to the procedure of Example 4starting with 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(RS)]azetidin-3-ol,0.15 cm³ of methanesulfonyl chloride and 0.6 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and methanol mixture (98/2 by volume) as eluents andcollecting 20 cm³ fractions. Fractions 8 to 13 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 8 cm³ of ethyl ether. 0.36 g of1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methylene]azetidineis obtained melting at 153° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 1.95 (4H, m, 2CH₂), 2.95 (3H, s, SCH₃), 3.20 (4H, m,2NCH₂), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 6.60(3H, m, 3CH arom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7 Hz, 4CHarom.), 7.48 (4H, d, J=7 Hz, 4CH arom.)].

1-Benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 0.77 g of3-pyrrolidinobenzyl methyl sulfone and 0.76 g of1-benzhydrylazetidin-3-one, 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(RS)]-azetidin-3-olare obtained in the form of a solid.

Methyl(3-pyrrolidinobenzyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 1 g of methyl(3-pyrrolidinobenzyl)sulfide and3.3 g of oxone^(R), 3.8 g of methyl(3-pyrrolidinobenzyl)sulfone isobtained in the form of a solid.

Methyl(3-pyrrolidinobenzyl)sulfide may be prepared in the followingmanner: a mixture of 2 g of (3-iodomenzyl)methylsulfide, 1.3 cm³ ofpyrrolidine, 1.1 g of sodium tert-butoxide, 0.28 g of1,1′-bis(diphenylphosphino)-ferrocenyl palladium chloride, 0.63 g of1,1′-bis(diphenyl)phosphino)ferrocene and 60 cm³ of tetrahydrofuran isheated under reflux, under a nitrogen stream, for 3 hours. The reactionmedium is cooled to room temperature and filtered on sintered glass. Theprecipitate is washed with 20 cm³ of tetrahydrofuran and 10 cm³ ofdichloromethane and then the filtrate is concentrated to dryness underreduced pressure (2.7 kPa). The residue is taken up with 30 cm³ of ethylacetate and 30 cm³ of 3 N hydrochloric acid. The aqueous phase isdecanted off, neutralized (ph=7-8) with 35 cm³ of 3 N Sodium hydroxideand taken up in 50 cm³ of ethyl acetate. The organic phase is extracted;4 g of silica are added and then the mixture is concentrated to drynessunder reduced pressure (2.5 kPa). The powder obtained is eluted onsintered glass containing 20 g of silica with a mixture of cyclohexaneand ethyl acetate (90/10 by volume). The filtrate is concentrated todryness under reduced pressure (2.7 kPa). 1.2 ofmethyl(3-pyrrolidinobenzyl)sulfide are obtained in the form of an oil.

1,1′-Bis(diphenylphosphino)ferrocenyl palladium chloride may be preparedaccording to Hayashi T. et al., J. Am. Chem. Soc., 106, 158 (1984).

EXAMPLE 38

Method 1

0.65 cm³ of methanesulfonyl chloride is added to a solution of 2.94 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olin 250 cm³ of dichloromethane at 22° C., followed, in small portionsover 15 minutes, by 2.42 g of 4-dimethylaminopyridine; theorange-colored solution is stirred for 2 hours at room temperature. Thereaction mixture is washed 3 times with 150 cm³ of distilled water andonce with 150 cm³ of a saturated sodium chloride solution and then driedwith magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm, height15 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (1/9 by volume) as eluents and collecting 70 cm³fractions. Fractions 15 to 36 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 1.86 g of white foam areobtained, which foam is crystallized from isopropyl ether in order toobtain a solid melting at 190° C. A recrystallization from 145 cm³ ofethanol gives 1.08 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemelting at 2062 C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm (300 MHz):3.00 (3H, s, SCH₃), 3.87 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s,NCH), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.), 7.45(4H, d, J=7 Hz, 4CH arom.)].

Method 2

0.08 g of sodium hydroxide is added to a solution of 2.2 g of3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidinein 25 cm³ of dioxane at room temperature. After 16 hours at roomtemperature, 50 cm³ of water and 100 cm³ of ethyl acetate are added. Themixture is separated after settling out, the organic phase rewashed with100 cm³ of water, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). A white foamis obtained which is crystallized from isopropyl ether in order toobtain 0.85 g of a solid melting at 190° C. Recrystallization from 20cm³ of ethanol gives 0.70 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemelting at 205° C.

EXAMPLE 39

6.75 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidine-3-olhydrochloride and then 2.97 g of potassium carbonate are added to asolution of 6.8 g of bis(4-chlorophenyl)bromomethane in 300 cm³ ofacetonitrile. The reaction mixture is heated for 1 hour under reflux,cooled to room temperature, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 8.5 cm, height22 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (25/75 by volume) as eluents and collecting 250 cm³fractions. Fractions 11 to 48 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 5.3 g of1-[(4-chlorophenyl)methyl]-(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained. [¹H NMR spectrum (300MHz, (CD₃)₂SO-d6, □ in ppm): 2.00 (s,3H), 2.94 (s, 3H), 3.25 (mt, 2H), 3.48 (d, J=9 Hz, 1H), 3.80 (d, J=9 Hz,1H), 4.54 (s, 1H), 5.34 (s, 1H), 7.15 (d, J=8.5 Hz, 2H), from 7.20 to7.40 (mt, 8H), 7.50 (broad t, J=9 Hz, 1H)].

Bis(4-chlorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).

3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride may be obtained in the following manner: 160 cm³ of a 6.2N hydrochloric acid solution in dioxane are added to a solution of 37 gof3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olin 160 cm³ of dioxane. After 16 hours at room temperature, the reactionmixture is concentrated to dryness under reduced pressure (2.7 kPa). Theresidue obtained is taken up in 320 cm³ of ethanol, heated for 1 hourunder reflux and cooled in an ice-cold water bath. The solid whichappears is filtered, washed with ethyl ether and dried at 40° C. underreduced pressure (2.7 kPa). 29.85 g of white crystals are obtained whosemelting point is greater than 260° C.

3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olmay be obtained in the following manner: a solution of 14.0 cm³ of vinylchloroformate in 35 cm³ of dichloromethane is added at 5° C. to asolution of 60.18 g of1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olin 1000 cm³ of dichloromethane. After 20 hours at room temperature, thereaction mixture is concentrated to dryness under reduced pressure (2.7kPa). The residue obtained is chromatographed on a silica gel column(particle size 0.04-0.06 mm, diameter 11 cm, height 32 cm), at an argonpressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (3.7by volume) as eluents and collecting 1000 cm³ fractions. Fractions 8 to18 are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 37 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olare obtained in the form of white crystals melting at 195° C.

EXAMPLE 40

14.3 cm³ of a 1.6 N n-butyllithium solution in hexane are added at -3170° C. to a solution of 4.77 g of (3,5-difluorobenzyl)methylsulfone in70 cm³ of tetrahydrofuran under an argon atmosphere. After 1 hour at−70° C., a solution of 6.8 g of1-[bis-4-chlorophenyl)methyl]azetidin-3-one in 30 cm³ of tetrahydrofuranis added and then, 1 hour later, a solution of 2.34 cm³ of acetylchloride in 20 cm³ of tetrahydrofuran and the temperature of thereaction mixture is raised to 20° C. for 1 hour. 50 cm³ of water and 20cm³ of ethyl acetate are added. The mixture is separated after settlingout, the organic phase washed with 100 cm³ of water, 100 cm³ of asaturated sodium solution, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). 14.4 g of3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylsulfonylmethyl-(RS)]azetidineare obtained in the form of a yellow oil [¹H NMR spectrum (400 MHz,CDCL₃, □ in ppm): 2.79 (s, 3H), 3.04 (AB, J=9 Hz, 2H), 3.27 (d, J=9 Hz,1H), 3.45 (s, 1H), 3.81 (d, J=9 Hz, 1H), 4.32 (s, 1H), 6.88 (tt, J=9 and2.5 Hz, 1H), from 7.20 to 7.35 (mt, 10H)].

1-Bis(4-chlorophenyl)methyl]azetidin-3-one may be prepared according tothe following procedure: a solution of 8.1 cm³ of dimethyl sulfoxide in17.6 cm³ of dichloromethane is added to a solution of 5.0 cm³ of oxalylchloride in 73 cm³ of dichloromethane cooled to −78° C. After 0.5 hourat −78° C., a solution of 16.0 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-ol dissolved in 50 cm³ ofdichloromethane is poured in. After 5 hours at −78° C., 26.6 cm³ oftriethylamine are added dropwise and the reaction mixture is allowed toreturn to room temperature. After 16 hours, the reaction mixture iswashed with 4 times 200 cm³ of water and then with 200 cm³ of asaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is chromatographed on a silica gel column (particlesize 0.04-0.06 mm, diameter 9.2 cm, height 21 cm) at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (40/60 byvolume) as eluents and collecting 200 cm³ fractions. Fractions 15 to 25are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 8.9 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one areobtained in the form of pale yellow crystals melting at 111° C.

1-[Bis(4-chlorophenyl)methyl]azetidin-3-ol may be prepared according tothe procedure described by KATRITZKY A. R. et al., J. Heterocycl. Chem.,(1994), 271 starting with 35.5 g of [bis(4-chlorophenyl)-methyl]aminehydrochloride and 11.0 cm³ of epichlorohydrin. 9.0 g of1-[bis(3-chlorophenyl)methyl]azetidin-3-ol are isolated.

[Bis(4-chlorophenyl)methyl]amine hydrochloride may be prepared accordingto the method described by GRISAR M. et al., J. Med. Chem., 885 (1973).

EXAMPLE 41

On carrying out the operation according to the procedure of Example 38(Method 1), starting with 0.72 g of1-bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-oland after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 4.0 cm, height 16.5 cm) at an argon pressure of 0.5 barwith a mixture of ethyl acetate and cyclohexane (2/8 by volume) aseluent and collecting 40 cm³ fractions, 0.10 g of a white foam isobtained. After crystallization from a mixture of ethyl acetate andcyclohexane, 60 mg of1-bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a solid melting at 180° C. [NMR spectrum inDMSO-d6, T=300K, □ in ppm (250 MHz): 3.00 (3H, s, SCH₃), 3.70 (6H, s, 2OCH₃), 3.80 (2H, s, NCH₂), 4.15 (2H, s, NCH₂), 4.85 (1H, s, NCH), 6.85(4H, d, J=7 Hz, 4CH arom.), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (5H,m, 5CH arom.)].

1-Bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to Example 39 starting with 1.2 g ofbis(4-methoxyphenyl)bromomethane and 1.2 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol ofhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.8 cm, height 18 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 50 cm³ fractions, fractions 9 to 18 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.55 g of1-bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained.

Bis(4-methoxyphenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).

EXAMPLE 42

On carrying out the operation according to Example 38 (Method 1),starting with 0.47 g of1-bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-oland after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 3.2 cm, height 18.5 cm), at an argon pressure of 0.5 barwith a mixture of ethyl acetate and cyclohexane (1/9 by volume) aseluent and collecting 35 cm³ fractions, 0.30 g of a white solid isobtained. After crystallization from diisopropyl ether, 0.20 g of1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of white needles melting at 200° C.

1-[Bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to Example 39 starting with 0.7 g ofbis(4-methylphenyl)bromomethane and 0.8 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol ofhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.0 cm, height 19 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 byvolume) as eluent and collecting 40 cm³ fractions, fractions 35 to 40are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.47 g of1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained.

Bis(4-methylphenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).

EXAMPLE 43

On carrying out the operation according to Example 38 (Method 1),starting with 1.42 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol,a mixture of the two diastereoisomers, and after chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 4.0 cm, height21 m), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (2/8 by volume) as eluent and collecting 40 cm³fractions, 0.10 g of a white solid is obtained. After crystallizationfrom diisopropyl ether, 50 mg of(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-(4-methoxyphenyl)(phenyl)methyl]azetidineare obtained in the form of a white solid [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 2.23 (6H, s, 2PhCH₃), 3.00 (3H, s, SCH₃),3.80 (2H, s, NCH₂), 4.12 (2H, s, NCH₂), 4.58 (1H, s, NCH), 7.08 (4H, d,J=7 Hz, 4CH arom.), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.25 (5H, m, 5CHarom.)].

The mixture of diastereoisomers3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to Example 39 starting with 2.52 g(RS)-bromo(4-methoxyphenyl)(phenyl)methane and 2.85 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 5.6 cm, height 19 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 100 cm³ fractions, fractions 11 to 18are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 1.16 g of the mixture of diastereoisomers3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-olare obtained.

(RS)-bromo(4-methoxyphenyl)(phenyl)methane may be prepared according tothe procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135(1933).

EXAMPLE 44

On carrying out the operation according to Example 38 (Method 1),starting with 0.47 g of1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,and after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 4.2 cm, height 14 cm), at an argon pressure of 0.5 bar witha mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent andcollecting 25 cm³ fractions, 0.28 g of1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a solid [NMR spectrum in DMSO-d6, T=300K, □in ppm (300 MHz): 3.05 (3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.90 (1H, s, NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.32 (5H, m,5CH arom.), 7.60 (4H, d, J=7 Hz, 4CH arom.)].

1-[Bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 50 cm³ fractions, fractions 15 to 23are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.49 g of1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-olis obtained.

Bis(4-trifluoromethoxyphenyl)bromomethane may be prepared according tothe procedure described by BACHMANN W. E., J. AM. Chem. Soc., 2135(1933), starting with 1.39 g of bis(4-trifluoromethoxyphenyl)methanol, 3cm³ of 33% hydrobromic acid in acetic acid and 0.6 cm³ of acetylbromide. 1.59 g of bis(4-trifluoromethoxyphenyl)bromomethane areobtained in the form of a brown oil.

Bis(4-trifluoromethoxyphenyl)methanol is prepared according to PAVIA M.R. et al., J. Med. Chem., 4238 (1992).

EXAMPLE 45

On carrying out the operation according to Example 38 (Method 1),starting with 0.25 g of1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,and after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 2.4 cm, height 14 cm), at an argon pressure of 0.5 bar witha mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent andcollecting 20 cm³ fractions, 0.12 g of1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 3.05 (3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.25(2H, s, NCH₂), 4.90 (1H, s, NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.32(5H, m, 5CH arom.), 7.60 (4H, d, J=7 Hz, 4CH arom.)].

1-[Bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationas in Example 39 starting with 1.46 g ofbis(4-trifluoromethylphenyl)bromomethane and 1.2 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 byvolume) as eluent and collecting 50 cm³ fractions, fractions 9 to 14 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.25 g of1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-olis obtained.

Bis(4-trifluoromethylphenyl)bromomethane may be prepared according tothe procedure described by BACHMANN W. E., J. AM. Chem. Soc., 2135(1933), starting with 2.5 g of bis(4-trifluoromethylphenyl)methanol, 6cm³ of 33% hydrobromic acid in acetic acid and 1.2 cm³ of acetylbromide. 2.9 g of bis(4-trifluoromethylphenyl)bromomethane are obtainedin the form of a brown oil.

Bis(4-trifluoromethylphenyl)methanol is prepared according to PAVIA M.R. et al., J. Med. Chem., 4238 (1992).

EXAMPLE 46

On carrying out the operation according to Example 38 (Method 2),starting with 3.16 g of3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonyl)methyl-(RS)}azetidineAND 0.96 g of ground sodium hydroxide, a yellow foam is obtained, after16 hours at room temperature, which is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 4.8 cm, height 14 cm), atan argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (15/85 by volume) as eluent and collecting 40 cm³ fractions.1.49 g of1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonyl)methylene}azetidineare thus obtained in the form of a white foam [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 3.05 (3H, s, SCH₃), 3.90 (2H, s, NCH₂), 4.30(2H, s, NCH₂), 4.80 (1H, s, NCH), 7.40 (2H, d, J=7 Hz, 2CH arom.), 7.50(2H, d, J=7 Hz, 2CH arom.), 8.10 (2H, s, 2CH arom.), 8.20 (1H, s, CHarom.)].

3-Acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonyl)methyl-(RS)}azetidinemay be obtained in the following manner: on carrying out the operationas in Example 40 starting with 2.0 g of[3,5-bis(trifluoromethyl)benzyl]methylsulfone, 4.1 cm³ of a 1.6 Nsolution of n-butyllithium in hexane, 2.0 g of1-[bis(4-chlorophenyl)methyl]azetidine-3-one and 0.77 cm³ of acetylchloride in 20 cm³ of anhydrous diisopropyl ether, 3.56 g of1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonyl)methyl-(RS)}azetidineare obtained in the form of a white foam after chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 5.6 cm, height16 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (1/9 by volume) as eluent and collecting 100 cm³fractions.

[3,5-Bis(trifluoromethyl)benzyl]methylsulfone is prepared in thefollowing manner: on carrying out the operation according to Example 10starting with 1.8 g of 3,5-bis(trifluoromethyl)benzyl chloride and 1.22g of sodium methanesulfinate, 1.86 g of[3,5-bis(trifluoromethyl)benzyl]methylsulfone are obtained in the formof a white solid.

EXAMPLE 47

On carrying out the operation according to Example 38 (Method 1),starting with 0.27 g of the mixture of the two diastereoisomers1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidine-3-oland after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 2.4 cm, height 7.5 cm), at an argon pressure of 0.5 barwith a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 20 cm³ fractions. 0.10 g of(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid [NMR spectrum in DMSO-d6,T=300K, □ in ppm (250 MHz): 3.02 (3H, s, SCH₃), 3.82 (1H, dd, J=3 and 16Hz, NCHH), 4.04 (1H, dd, J=3 and 16 Hz, NCHH), 4.10 (1H, dd, J=3 and 16Hz, NCHH), 4.35 (1H, dd, J=3 and 16 Hz. NCHH), 5.12 (1H, s, NCH), 7.18(2H, d, J=8 Hz, 2CH arom.), 7.32 (1H, t, J=8 Hz, CH arom.), 7.38 (2H, d,J=7 Hz, 2CH arom.), 7.45 (2H, d, J=7 Hz, 2CH arom.), 7.48 (1H, dd, J=2and 7 Hz, CH arom.), 7.58 (1H, d, J=2 Hz, CH arom.), 7.80 (1H, d, J=7Hz, CH arom.)].

The mixture of the two diastereoisomers1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidine-3-olmay be obtained in the following manner: on carrying out the operationaccording to Example 39 starting with 0.56 g(RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane and 0.50 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.0 cm, height 13 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 byvolume) as eluent and collecting 40 cm³ fractions, fractions 9 to 14 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.27 g of the mixture of the two diastereoisomers1-[(4-chlorophenyl)(2,4-dichlorophenyl)methane may be prepared accordingto the procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135(1933) starting with 4.05 g of(RS)-(4-chlorophenyl)(2,4-dichlorophenyl)methanol, 10 cm³ of 33%hydrobromic acid in acetic acid and 2.1 cm³ of acetyl bromide. 4.6 of(RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane are obtained inthe form of a greenish oil.

(RS)-(4-chlorophenyl)(2,4-dichlorophenyl)methanol is prepared accordingto PAVIA M. R. et al., J. Med. Chem., 4238 (1992).

EXAMPLE 48

75.6 cm³ of 5 N hydrochloric acid are added to a solution of 18.9 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 80 cm³ of tetrahydrofuran. After 3 hours at room temperature, themixture is taken up in dichloromethane and distilled water and thenadjusted to pH 14 by addition of 30% sodium hydroxide and separatedafter settling out. The organic phase is washed twice with 100 cm³ofwater and then 100 cm³ of a saturated aqueous sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). 16 g of(RS)-1-[(4-chlorophenyl)(4-formylphenyl)methyl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a white foam [Spectrum in DMSO-d6, T=300K, □in ppm (300 MHz): 3.06 (3H, s, SCH₃), 3.95 (2H, m, NCH₂), 4.26 (2H, m,NCH₂), 4.91 (1H, s, NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.36 (1H, t,J=8 Hz, 1CH arom.), 7.40 and 7.52 (4H, 2d, J=7.5 Hz, 4CH arom.), 7.70and 7.88 (4H, 2d, J=7.5 Hz, 4CH arom.), 9.97 (1H, s, CH aldehydic)].

1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemay be prepared according to the following method: 13.0 cm³ of1.8-diazabicyclo[5.4.0]under-7-ene are added dropwise to a solution of34.45 g of the mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidinein 400 cm³ of tetrahydrofuran under argon at 0° C., and after customarytreatment, 16.6 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a white solid after chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 10.2 cm, height23 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (2.8 by volume) as eluent and collecting 250 cm³fractions.

The mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidinemay be obtained in the following manner: on carrying out the operationaccording to Example 40, starting with 11.6 g of(3,5-difluorobenzyl)methylsulfone, 35.1 cm³ of a 1.6 N solution ofn-butyllithium in hexane, 19.3 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-oneand 8.8 cm³ of acetyl chloride in 500 cm³ of tetrahydrofuran, 37.8 g ofthe mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidineare obtained in the form of a white foam.

1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-onemay be prepared in the following manner: 46 cm³ of triethylamine areadded at room temperature to a solution of 28.32 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-olin 200 cm³ of dimethyl sulfoxide, and then a solution of 34 g of sulfurtrioxide-pyridine complex in 100 cm³ of dimethyl sulfoxide are addeddropwise. After 0.25 hour at room temperature, the reaction mixture ispoured over ice, extracted with ethyl acetate, washed with 3 times 400cm³ of water and then with 400 cm³ of a saturated sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure (2.7 kPa). The residue obtained ischromatographed on a silica gel column (particle size 0.04-0.06 mm,diameter 9.2 cm, height 21 cm), at an argon pressure of 0.5 bar with amixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent andcollecting 250 cm³ fractions. Fractions 9 to 18 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-oneare obtained in the form of a yellow oil.1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-olmay be prepared according to the procedure described by KATRITZKY A. R.et al., J. Heterocycl. Chem., 271 (1994) starting with 35.0 g of{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine, 8.3 g ofepibromohydrin, 5.1 g of sodium hydrogen carbonate and 400 cm³ ofethanol. 30.3 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-olare isolated.

{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}aminehydrochloride may be prepared according to the method described byGRISAR M. et al., J. Med. Chem., 885 (1973) starting with 67.2 g of1-(1,3-dioxolan-2-yl)benzonitrile, 88.2 g of 1-bromo-4-chlorobenzene, 11g of magnesium and 600 cm³ of ethyl ether. 42.3 g of{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}amine areobtained in the form of a yellow oil.

EXAMPLE 49

0.020 g of sodium borohydride is added to a solution of 0.50 g of(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 15 cm³ of methanol at 02 C. After 1 hour at 0° C., 40 cm³ of waterare added and the product extracted with 100 cm³ of dichloromethane. Theorganic phase is washed twice with 40 cm³ of water and then 40 cm³ of asaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is chromatographed on a silica gel column (particlesize 0.04-0.06 mm, diameter 3.2 cm, height 14 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 byvolume) and collecting 20 cm³ fractions. Fractions 20 to 25 are combinedand then concentrated to dryness under reduced pressure (2.7 kPa). 0.29g of(RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white foam [NMR spectrum in DMSO-d6,T=300K, □ in ppm (250 MHz): 3.02 (3H, s, SCH₃), 3.90 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.42 (2H, d, J=5 Hz, OCH₂), 4.75 (1H, s, NCH), 5.10 (1H,t, J=5 Hz, OH), between 7.10 and 7.50 (11H, m, 11CH arom.)].

EXAMPLE 50

0.75 g of(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineand then 0.68 g of sodium triacetoxyborohydride are added to a solutionof 0.10 g of pyrrolidine in 20 cm³ of 1,2-dichloroethane. After 20 hoursat room temperature, 2 cm³ of 1 N sodium hydroxide are added, theproduct is extracted with 100 cm³ of dichloromethane, the organic phaseis washed twice with 50 cm³ of water and then 50 cm³ of a saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of0.5 bar with acetate as eluent and collecting 20 cm³ fractions.Fractions 10 to 18 are combined and then concentrated to dryness underreduced pressure (2.7 kPa). 0.39 g of(RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white foam [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 1.65 (4H, m, 2CH₂), 2.40 (4H, m, 2NCH₂),3.02 (3H, s, SCH₃), 3.50 (2H, s, NCH₂Ph), 3.85 (2H, s, NCH₂), 4.20 (2H,s, NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.40 (9H, m, 9CH arom.),7.48 (2H, d, J=7 Hz, 2CH arom.)].

EXAMPLE 51

On carrying out the operation as in Example 50 starting with 0.93 cm³ ofa 2 M solution of dimethylamine in methanol, 30 cm³ of1,2-dichloroethane, 0.75 g of(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineand then 0.9 g of sodium triacetoxyborohydride, there is obtained afterchromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 17.5 cm), at an argon pressure of 0.5 bar with amixture of ethyl acetate and cyclohexane (30/70 by volume) as eluent andcollecting 40 cm³ fractions, 0.46 g of(RS)-1-[(4-chlorophenyl)(4-dimethylaminomethyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein the form of a white solid [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 2.12 (6H, s, N(CH₃)₂), 3.02 (3H, s, SCH₃), 3.32 (2H, s,NCH₂Ph), 3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.18(2H, d, J=8 Hz, 2CH arom.), 7.22 (2H, d, J=8 Hz, 2CH arom.), 7.35 (1H,t, J=8 Hz, CH arom.), 7.39 (4H, m, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4CHarom.)].

EXAMPLE 52

A solution of 0.5 g of(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 10 cm³ of dichloromethane at 0° C. is stirred with 0.5 cm³ of asolution (2 M) of dimethylamine in ethanol. 13 mg ofhydroxybenzotriazol, 0.2 g of1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride and 0.18 cm³of diisopropylethylamine are then added. After 20 hours at roomtemperature, the reaction mixture is diluted with dichloromethane,washed twice with 80 cm³ of water and then 80 cm³ of a saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of0.5 bar with a dichloromethane/acetonitrile/methanol (98/1/1 by volume)mixture as eluent and collecting 15 cm³ fractions. Fractions 13 to 15are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.16 g of a cream-colored solid is obtained which, aftertaking up in isopropyl ether and drying, gives 0.11 g of(RS)-1-{(4-chlorophenyl)[(4-N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein the form of a solid [NMR spectrum in DMSO-d6, T=300K, □ in ppm (300MHz): 2.85 (3H, broad s, NCH₃)₂), 2.95 (3H, broad s, NCH₃), 3.00 (3H, s,SCH₃), 3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.15(2H, d, J=8 Hz, 2CH arom.), 7.30 (1H, t, J=8 Hz, 2CH arom.), 7.35 (4H,m, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.)].

(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: 1.0 cm³ of Jones reagent isadded to a solution of 0.50 g of(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 10 cm³ acetone at 0° C. After 5 hours, the reaction mixture is pouredinto distilled water, the product is extracted with 50 cm³ of ethylacetate, the organic phase is washed twice with 50 cm³ of water and then50 cm³ of a saturated sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from an ethylacetate-cyclohexane mixture, filtered and dried. 0.50 g of(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid.

EXAMPLE 53

The operation is carried out as in Example 52, starting with 1 g of(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,0.38 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22mg of hydroxybenzotriazole hydrate, 30 cm³ of dichloromethane and 0.83cm³ of a 2 M ethylamine solution in THF, chromatographing on a silicagel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 15 cm),at an argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (45/55 by volume) as eluent and collecting 30 cm³ fractions.Fractions 22 to 32 are combined and then concentrated to dryness underreduced pressure (2.7 kPa). 0.29 g of(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbomyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 1.07 (3H, t, J=6 Hz, CH₃), 3.00 (3H, s,SCH₃), 3.35 (2H, m, NCH₂), 3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80(1H, s, NCH), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (1H, t, J=8 Hz, 2CHarom.), 7.35 (2H, d, J=7 Hz, 2CH arom.), 7.48 (4H, m, 4CH arom.), 7.74(2H, d, J=7 Hz, 2CH arom.), 8.37 (1H, t, CONH)].

EXAMPLE 54

The operation is carried out as in Example 52, starting with 1 g of(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,0.38 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22mg of hydroxybenzotriazole hydrate, 40 cm³ of dichloromethane and 0.24cm³ of a 7 N solution of ammonium hydroxide in methanol andchromatographing on a silica gel column (particle size 0.04-0.06 mm,diameter 4.1 cm, height 15 cm), at an argon pressure of 0.5 bar with amixture of ethyl acetate and cyclohexane (60/40 by volume) as eluent andcollecting 35 cm³ fractions. Fractions 38 to 48 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.29 g ofsolid is obtained which, after taking up in isopropyl ether and drying,gives 0.22 g of(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein the form of a white solid [NMR spectrum in DMSO-d6, T=300K, □ in ppm(300 MHz): 3.00 (3H, s, SCH₃, 3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.82 (1H, s, NCH), 7.17 (2H, d, J=8 Hz, 2CH arom.), 7.30 (1H, t, J=8 Hz,CH arom.), 7.38 (2H, d, J=7 Hz, 2CH arom.), 7.50 (5H, m, 4CH arom. and 2CONH₂), 7.80 (2H, d, J=7 Hz, 2CH arom.), 7.90 (1H, s, 2 CONH₂)].

EXAMPLE 55

The operation is carried out according to the procedure of Example 4starting with 1.7 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.35 cm³ of methanesulfonyl chloride and 1.5 g of4-dimethylaminopyridine. The residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol (99.5/0.5 by volume) as eluentand collecting 100 cm³ fractions. Fractions 7 to 10 are combined andthen concentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 15 cm³ of ethyl ether. 0.2 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidineis obtained melting at 200° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 3.00 (3H, s, SCH ₃), 3.80 (3H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (6H, m,6CH arom.), 7.67 (1H, s, CH arom.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 39 starting with 4 g ofbis(4-chlorophenyl)bromomethane and 3 g of3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride, the residue obtained is purified by chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 40cm), at a nitrogen pressure of 0.5 bar with dichloromethane and then amixture of dichloromethane and ethanol (99/1 by volume) as eluent andcollecting 100 cm³ fractions. Fractions 15 to 19 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 1.7 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

Bis(4-chlorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).3-[(3,5-Dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride may be obtained in the following manner: on carrying outthe operation according to the procedure of Example 39 starting with 5.6g of3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-oland 56 cm³ of a 6.2 N solution of hydrochloric dioxane in 56 cm³ ofdioxane, 5.1 g of3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol ofhydrochloride are obtained in the form of a foam.

3-[(3,5-Dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olmay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 39 starting with 7.4 g of1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-azetidin-3and1.6 cm³ of vinyl chloroformate in 75 cm³ of dichloromethane, the residueobtained is purified by chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 3 cm, height 40 cm), at a nitrogen pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 byvolume) as eluent and collecting 100 cm³ fractions. Fractions 4 to 10are combined and concentrated to dryness under reduced pressure (2.7kPa). 5.6 g of3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olare obtained in the form of a foam.

EXAMPLE 56

On carrying out the operation according to the procedure of Example 4starting with 0.5 g of1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3ol,0.1 cm³ of methanesulfonyl chloride and 0.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol (98/2 by volume) as eluent andcollecting 20 cm³ fractions. Fractions 8 to 13 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 8 cm³ of ethyl ether. 0.3 g of1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methylene]azetidineis obtained melting at 176° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (250 MHz): 2.90 (6H, s, N(CH₃)_(2),) 2.95 (3H, s, SCH₃), 3.80 (2H,s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 6.70 (3H, m, 3CHarom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.48(4H, d, J=7 Hz, 4CH arom.)].

1-Benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 0.4 g of(3-dimethylaminobenzyl)methylsulfone, 0.4 g of1-benzhydrylazetidin-3-one and 1.2 cm³ of a 1.6 M solution ofn-butyllithium in hexane, 0.5 g of1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained in the form of a solid.

(3-Dimethylaminobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 1.4 g of (3-dimethylaminobenzyl)methylsulfideand 5.1 g of oxone^(R), 1.1 g of (3-dimethylaminobenzyl)methylsulfoneare obtained in the form of a white solid melting at 195° C.

(3-Dimethylaminobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 37 starting with 4 g of (3-iodobenzyl)methylsulfide, 1.4 g ofdimethylamine in solution in 5 cm³ of tetrahydrofuran, 2.9 g of sodiumtertbutoxide, 0.56 g of 1,1-bis(diphenylphosphino)ferrocenylpalladiumchloride and 1.3 g of 1,1′-bis(diphenylphosphino)ferrocene in 35 cm³ oftetrahydrofuran, 0.9 g of (3-dimethylaminobenzyl)methylsulfide isobtained in the form of an oil.

EXAMPLE 57

On carrying out the operation according to the procedure of Example 4starting with 1.3 g of1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 1.4 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol (98/2 by volume) as eluent andcollecting 20 cm³ fractions. Fractions 11 to 13 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 15 cm³ of ethyl ether. 0.6 g of1-benzhydryl-3-[3-(methylsulfanylphenyl)(methylsulfonyl)methylene]azetidineis obtained melting at 146° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 2.45 (3H, s, PhSCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), between 7.10 and 7.50(14H, m, 14CH arom.)].

1-Benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 1.1 g ofmethyl(3-methylsulfanylbenzyl)sulfone, 1.2 g of1-benzhydrylazetidin-3-one, 1.3 g of1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a solid.

Methyl(3-methylsulfanylbenzyl)sulfone may be prepared in the followingmanner: a mixture of 5 g of (3-iodobenzyl)methylsulfone and 1 g oftetrakistriphenylphosphinepalladium in 250 cm³ of dimethyl sulfoxide isheated at a temperature close to 100° C., under a nitrogen stream, for 1hour. 2.5 g of sodium methylthiolate are added and then the heating at100° C. is maintained for 18 hours. The reaction medium is cooled toroom temperature and taken up in 700 cm³ of ethyl acetate and 500 cm³ ofwater. The organic phase is decanted off, washed with 10 times 500 cm³of water, 500 cm³ of a saturated aqueous sodium chloride solution,filtered on sintered glass and concentrated to dryness under reducedpressure (2.7 kPa). The residue obtained is purified by chromatographyon a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm,height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture ofcyclohexane and ethyl acetate (70/30 and then 60/40 and then 50/50 byvolume) as eluent and collecting 30 cm³ fractions. Fractions 26 to 30are combined and concentrated to dryness under reduced pressure (2.7kPa). 1.2 g of methyl(3-methylsulfanyl-benzyl)methylsulfone are obtainedin the form of an oil.

EXAMPLE 58

4 cm³ of a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, cooled to 5° C., of 1.1 g1-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}azetidinein 10 cm³ of tetrahydrofuran. The mixture is stirred for 3 hours at atemperature close to 20° C. and then taken up in 100 cm³ of ethylacetate and twice 50 cm³ of water. The organic phase is decanted off,extracted, dried over anhydrous magnesium sulfate and concentrated todryness under reduced pressure (2.7 kPa). The residue obtained ispurified by chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of0.5 bar with a mixture of dichloromethane and ethanol (95/5 by volume)as eluent and collecting 60 cm³ fractions. Fractions 4 to 6 are combinedand concentrated to dryness under reduced pressure (2.7 kPa). 0.5 g of1-benzhydryl-3-[(3-(hydroxymethylphenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid melting at 152° C. [NMRspectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 2.95 (3H, s, SCH ₃),3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.50 (2H, d, J=5 Hz, OCH₂), 4.75(1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.20 (2H, t, J=7 Hz, 2CH arom.),7.30 (8H, m, 8CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].

1-Benzhydryl-3-{[3-tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidinemay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 1.6 g of1-benzhydryl-3-{[3-tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methylsulfonyl chloride and 1.4 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 60 cm³ fractions. Fractions 15 to 30 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 1.1 g of1-benzhydryl-3-{[3-tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}azetidineare obtained in the form of a white solid melting at 148° C.

1-Benzhydryl-3-{[3-tert-butyldimethylsilyloxymethyl)phenyl]-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2 g of[3-(tert-butyldimethylsilyloxymethyl)benzyl]methylsulfone and 1.5 g of1-benzhydrylazetidin-3-one, 1.6 g of1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid melting at 1752 C.

[(3-Tert-butyldimethylsilyloxy-methyl)benzyl]methylsulfone may beprepared in the following manner: a mixture of 13.4 g of(3-hydroxymethylbenzyl)methylsulfone, 11 g of imidazole and 12 g oftert-butyldimethylsilane chloride is stirred for 18 hours at atemperature close to 20° C. The solution is concentrated to drynessunder reduced pressure (2.7 kPa). The residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 5 cm, height 50 cm), at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 7to 14 are combined and concentrated to dryness under reduced pressure(2.7 kPa). 5.7 g of[3-(tert-butyldimethylsilyloxymethyl)benzyl]methylsulfone are obtainedin the form of a white solid melting at 80° C.

(3-Hydroxymethylbenzyl)methylsulfone may be prepared in the followingmanner: a mixture of 26 g of 3-(methylsulfonylmethyl)benzoic acid and4.6 g of lithium aluminium hydride in 600 cm³ of tetrahydrofuran isstirred for 18 hours at a temperature close to 20° C. The solution iscooled to 0° C. and then 15 cm³ of ethyl acetate, 5 cm³ of water, 5 cm³of a 15% aqueous solution of sodium hydroxide and finally 30 cm³ ofwater are added successively. The mixture is filtered on celite, thefiltrate taken up in 600 cm³ of ethyl acetate. The organic phase istaken up in 500 cm³ of water and then 200 cm³ of a saturated aqueoussodium chloride solution, decanted off, dried over anhydrous magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kPa). 10.4 g of (3-hydroxymethylbenzyl)methylsulfone are obtainedin the form of a gum.

3-Methylsulfonylmethyl)benzoic acid may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 10 starting with 23.3 g of 3-chloromethylbenzoic acid and 23.3 gof sodium methanesulfinate, 26 g of 3-(methylsulfonylmethyl)benzoic acidare obtained in the form of a white solid melting at 210° C.

EXAMPLE 59

0.13 g of sodium methylthiolate is added, while the temperature ismaintained below 30° C., to a solution of 0.8 g of1-benzhydryl-3-[(3-bromomethylphenyl)(methylsulfonyl)methylene]azetidinein 8 cm³ of dimethylformamide. The mixture is stirred for 18 hours at atemperature close to 20° C. and then taken up in 30 cm³ of ethyl acetateand 50 cm³ of water. The organic phase is decanted off, extracted andwashed with 3 times 50 cm³ of water, dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is purified by chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 2 cm, height 28 cm) at a nitrogen pressureof 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10 byvolume) as eluent and collecting 50 cm³ fractions. Fractions 8 to 14 arecombined and concentrated to dryness under reduced pressure (2.7 kPa).0.3 g of1-benzhydryl-3-{[3-(methylsulfanylmethyl)phenyl](methylsulfonyl)methylene]}azetidineis obtained in the form of a white solid melting at 150° C. [NMRspectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 1.95 (3H, s, SCH₃),2.95 (3H, s, SCH₃), 3.75 (2H, s, SCH₂), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, CH arom.), 7.30 (8H, d,J=7 Hz, 8CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].

1-Benzhydryl-3-[(3-(bromomethylphenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: 0.23 cm³ of phosphorustribromide and then a drop of pyridine are added, at a temperature closeto 20° C., to a mixture of 1 g of1-benzhydryl-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidinein 10 cm³ of dichloromethane. The stirring is maintained for 18 hours atthe same temperature. The reaction medium is taken up in 20 cm³ of waterand 10 cm³ of a saturated aqueous sodium chloride solution. The organicphase is decanted off, extracted, dried over anhydrous magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kPa). 1 g of1-benzhydryl-3-[(3-(bromomethylphenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a foam used in the crude state in subsequentsyntheses.

EXAMPLE 60

On carrying out the operation according to the procedure of Example 4starting with 6.6 g of1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]azetidin-3-ol,1.7 cm³ of methanesulfonyl chloride and 5.2 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6.5 cm, height 35 cm), at a nitrogen pressure of 0.5 bar with adichloromethane and methanol mixture (95/5 by volume) as eluent andcollecting 40 cm³ fractions. Fractions 7 to 15 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 100 cm³ of ethyl ether. 4.4 g of1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methylene]azetidine areobtained melting at 2122 C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm(250 MHz): 3.15 (3H, s, SCH₃), 3.55 (2H, broad s, NCH₂), 4.30 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.18 (2H, t, J=7 Hz, 2CH arom.), 7.25 (4H, t,J=7 Hz, 4CH arom.), 7.43 (4H, d, J=7 Hz, 4 CH arom.), 7.62 (2H, m, 2CHquinoline), 7.75 (1H, dd, J=2 and 7 Hz, CH quinoline), 8.05 (1H, dd, J=2and 7 Hz, CH quinoline), 8.43 (1H, dd, J=2 and 8 Hz, CH quinoline), 9.00(1H, dd, J=2 and 5 Hz, CH quinoline)].1-Benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 5.5 g ofmethyl(quinol-8-ylmethyl)sulfone, 5.9 g of 1-benzhydrylazetidin-3-oneand 18.8 cm³ of a 1.6 M solution of n-butyllithium in hexane, 6.6 g of1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]azetidin-3-olare obtained in the form of a beige solid.

Methyl(quinol-8-ylmethyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 10 starting with 4.5 g of 8-chloromethylquinoline and 4.4 g ofsodium methanesulfinate, 5.7 g of methyl(quinol-8-ylmethyl)sulfone areobtained in the form of a beige solid.

8-Chloromethyl quinoline may be prepared in the following manner: 6.7 gof N-chlorosuccinimide and the 250 mg of benzoyl peroxide are added, ata temperature close to 20° C., to a mixture of 7.1 g of8-methylquinoline in 250 cm³ of carbon tetrachloride. The reactionmedium is heated at the reflux temperature of the solvent for 36 hoursand then cooled to 20° C. The mixture is filtered on sintered glass andthe filtrate is concentrated to dryness under reduced pressure (2.7kPa). The residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 5.5 cm, height 32 cm), at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 40 cm³ fractions. Fractions 21 to 40 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 4.5 g of-8-chloromethyl-quinoline are obtained in the form of a brown oil whichis used in the crude state in subsequent synthesis.

EXAMPLE 61

On carrying out the operation according to the procedure of Example 4starting with 6.2 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.3 cm³ of methanesulfonyl chloride and 6.1 g of 4dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 4 cm, height 60 cm), at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 100 cm³ fractions. Fractions 4 to 7 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 25 cm³ of ethyl ether. 0.7 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a solid melting at 178° C. [NMR spectrum inDMSO-d6, T=300K, □ in ppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.30 (4H, d, J=7 Hz, 4CHarom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 7.60 (1H, t, J=7 Hz, CH arom.),7.70 (1H, d, J=7 Hz, CH arom.), 7.85 (2H, m, 2CH arom.)].1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 5.5 g of(3-cyanophenyl)-methylsulfone, 6.1 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 13.8 cm³ of a 1.6 Msolution of n-butyllithium in hexane, 6.3 g of1-[bis-(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

EXAMPLE 62

A mixture of 4.5 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidinein 50 cm³ of acetic acid and 50 cm³ of concentrated hydrochloric acid(d=1.18) is heated at 50° C. for 20 hours. The reaction medium is cooledto room temperature and concentrated to dryness under reduced pressure(2.7 kPa). The oil obtained is taken up in 100 cm³ of ethanol and thenthe solution is concentrated to dryness under reduced pressure (2.7kPa). The residue is precipitated in 60 cm³ of ethyl ether. The solidobtained is purified by chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 25 cm, height 40 cm) at a nitrogen pressureof 0.5 bar with dichloromethane and then a dichloromethane and ethanolmixture (99.5/0.5 by volume) as eluent and collecting 30 cm³ fractions.Fractions 35 to 46 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from 15cm³ of ethyl ether. 0.2 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a solid melting at 192° C. [NMR spectrum inDMSO-d6, T=300K, □ in ppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CHarom.), 7.45 (5H, d, J=7 Hz, 4CH arom. and 2 CONH₂), 7.50 (2H, m, 2CHAROM.). 7.85 (2H, m, 2CH arom.)].

EXAMPLE 63

On carrying out the operation according to the procedure of Example 1starting with 0.8 g of1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3ol,0.2 cm³ of methanesulfonyl chloride and 0.7 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size (0.04-0.06 mm,diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with adichloromethane and ethanol mixture (98/2 by volume) as eluent,collecting 20 cm³ fractions. Fractions 4 to 8 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is recrystallized from 10 cm³ of ethyl acetate, 0.5 g of1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}-azetidineis obtained in the form of a solid melting at 161° C. [NMR spectrum inDMSO-d6, T=300K, □ in ppm (300 MHz): 1.30 (9H, s, (CH₃)₃ ), 2.95 (3H, s,SCH₃), 3.15 (3H, s, NCH₂), 3.75 (2H, s, SCH₂), 3.80 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.50 (14H, m, 14CHarom.)].

1-Benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 1.6 of[3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 1.3 g of1-benzhydrylazetidin-3-one and 3.8 cm³ of a 1.6 M solution ofn-butyllithium in hexane, 0.8 g of1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-olis obtained in the form of a white solid.

[3-(N-tert-butyloxycarbonyl-N-methylamino)methylsulfone may be preparedin the following manner: 2.5 g of di-tert-butyl dicarbonate in 40 cm³ ofdioxane are added to a solution, cooled to 0° C. ofmethyl(3-methylaminobenzyl)sulfone in 30 cm³ of dioxane. The stirring ismaintained for 18 hours at room temperature. The reaction medium istaken up in 75 cm³ of dichloromethane; the organic phase is washed with75 cm³ of water and then with 75 cm³ of a saturated aqueous sodiumchloride solution. The organic phase is decanted off, extracted, driedover anhydrous sodium sulfate, filtered and concentrated to drynessunder reduced pressure (2.7 kPa). The residue obtained is purified bychromatography on a silica gel column (particle size (0.04-0.06 mm,diameter 2 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with acyclohexane and ethyl acetate mixture (50/50 by volume) as eluent,collecting 20 cm³ fractions. Fractions 5 to 10 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of[3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone areobtained in the form of a colorless oil.

Methyl(3-methylaminobenzyl)sulfone may be prepared in the followingmanner: a mixture of 9.7 cm³ of formic acid (d=1.22) and 19.6 cm³ ofacetic anhydride (d=1.08) is heated for 3 hours at 50° C. and then thesolution is allowed to return to room temperature. 40 cm³ oftetrahydrofuran are added and the mixture is cooled to −20° C. 14.8 g of(3-aminobenzyl)methylsulfone and 200 cm³ of tetrahydrofuran are thenadded. The stirring is maintained for 2 hours at −20° C. and then 48hours at room temperature. The mixture is filtered on sintered glass,the precipitate is washed with 3 times 50 cm³ of diisopropyl ether andthen dried. The filtrate is concentrated to half its volume (2.7 kPa),the precipitate obtained is filtered on sintered glass and washed with 3times 30 cm³ of diisopropyl ether and then dried. The two precipitatesare combined and dissolved in 375 cm³ of tetrahydrofuran. The solutionis cooled to 0° C.; 100 cm³ of a 2 M solution of borane dimethyl sulfidein tetrahydrofuran added and then heated under reflux for 3 hours. Themixture is cooled to 5° C. and then 60 cm³ of methanol are added over 20minutes. The stirring is maintained for 1 hour at room temperature. Astream of hydrogen chloride is bubbled in the solution for 5 minutes.The reaction medium is then heated under reflux for 1 hour, cooled toroom temperature and taken up in 300 cm³ of water. The solution isalkalinized with 3N sodium hydroxide a then with a saturated aqueoussodium bicarbonate solution. The organic phase is extracted with twice250 cm³ of ethyl acetate, washed with 30 cm³ of a saturated aqueoussodium bicarbonate solution and twice 300 cm³. It is concentrated todryness under reduced pressure (2.7 kPa). The oil obtained is taken upin 100 cm³ of 4 N hydrochloric acid and then with 100 cm³ of ethylacetate. The aqueous phase is alkalinized with 120 cm³ of 3 N sodiumhydroxide, and then with an aqueous sodium bicarbonate solution. Theorganic phase is extracted with twice 75 cm³ of ethyl acetate, driedover anhydrous magnesium sulfate, filtered and concentrated to drynessunder reduced pressure (2.7 kPa). 9 g ofmethyl(3-methylaminobenzyl)sulfone are obtained in the form of a pinksolid.

(3-Aminobenzyl)methylsulfone may be prepared in the following manner: amixture of 23.7 g of methyl(3-nitrobenzyl)sulfone, 65 cm³ ofhydrochloric acid (d=1.18) and 150 cm³ of methanol is heated underreflux for 15 minutes. 18.5 g of iron are added over 10 minutes and thereflux is maintained for 4 hours and then 18 hours at room temperature.The reaction medium is alkalinized with an aqueous solution of ammoniumhydroxide and then with an aqueous sodium bicarbonate solution. Theorganic phase is extracted with 3 times 250 cm³ of ethyl acetate, driedover magnesium sulfate, filtered on sintered glass and concentrated todryness under reduced pressure (2.7 kPa). 14.9 g of(3-aminobenzyl)methylsulfone are obtained in the form of a beige solidwhich is used in the crude state in subsequent synthesis.

EXAMPLE 64

A mixture of 0.3 g of1-benzhydryl-3-{[(3-N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidine,4 cm³ of a 4.7 N solution of hydrochloric dioxane and 4 cm³ of dioxaneis stirred for 18 hours at room temperature. The reaction medium isconcentrated to dryness under reduced pressure (2.7 kPa). The residue istaken up in 100 cm³ of water and 20 cm³ of diethyl ether. The aqueousphase is alkalinized with 30 cm³ of an aqueous sodium bicarbonatesolution. The organic phase is extracted with twice 40 cm³ of ethylacetate, washed with twice 30 cm³ of water, decanted off, dried overanhydrous magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue is crystallized from 20 cm³ ofdiethyl ether. 0.16 g of1-benzhydryl-3-[(3-methylaminophenyl)((methylsulfonyl)methylene]azetidineis obtained in the form of a solid melting at 161° C. [NMR spectrum inDMSO-d6, T=300K, □ in ppm (250 MHz): 2.65 (3H, d, J=5 Hz, NCH₃), 2.95(3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s,NCH), 5.80 (1H, q, J=5 Hz, NH), 6.60 (3H, m, 3CH arom.), 7.15 (1H, t,J=7 Hz, CH arom.), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom, 7.48 (4H, d, J=7 Hz, 4 CH arom.)]. cl EXAMPLE 65

On carrying out the operation according to the procedure of Example 4starting with 11.3 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,2.6 cm³ of methanesulfonyl chloride and 10.9 g of4-dimethylaminopyridine, 5 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidineare obtained after recrystallization from 20 cm³ of diethyl ether,melting at 181° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm (300 MHz):2.95 (3H, s, SCH₃), 3.76 (3H, s, OCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.80 (1H, s, NCH), 6.95 (3H, m, 3CH arom.), 7.35 (5H, m, 5CHarom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].1-[Bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 6.6 g of(3-methoxybenzyl)methylsulfone, 10 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 23 cm³ of a 1.6 Nsolution of n-butyllithium in hexane, 11.4 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid melting at 130° C.

EXAMPLE 66

On carrying out the operation according to the procedure of Example 32starting with 4.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,32 cm³ of a 1 M solution of boron tribromide in dichloromethane, theresidue obtained is purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at a nitrogenpressure of 0.5 bar with a mixture of dichloromethane and ethanol (98/2by volume) as eluent and collecting 20 cm³ fractions. Fractions 16 to 17are concentrated to dryness under reduced pressure (2.7 kPa). 0.1 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidinis obtained, after recrystallization from 5 cm³ of diethyl ether, in theform of a solid melting at 114° C. [NMR spectrum in DMSO-d6, T=300K, □in ppm (250 MHz): 2.92 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.80 (1H, s, NCH), 6.80 (3H, m, 3CH arom.), 7.20 (1H, t, J=7 Hz,CH arom.), 7.37 (4H, t, J=7 Hz, 4CH arom.), 7.47 (4H, d, J=7 Hz, 4 CHarom.)].

EXAMPLE 67

On carrying out the operation according to the procedure of Example 4starting with 0.6 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3ol,0.1 cm³ of methanesulfonyl chloride and 0.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and ethanol mixture as eluent (98.5/1.5 by volume) andcollecting 10 cm³ fractions. Fraction 4 is concentrated to dryness underreduced pressure (2.7 kPa). 0.5 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methylene]azetidineis obtained, after recrystallization from 5 cm³ of diethyl ether in theform of a solid melting at 133° C. [NMR spectrum in DMSO-d6, T=300K, □in ppm (400 MHz): 2.00 (4H, m, 2 CH₂), 2.95 (3H, s, SCH₃), 3.20 (4H, m,2 NCH₂), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 6.50(1H, s, CH arom.), 6.60 (1H, d, J=7 Hz, CH arom.), 6.65 (1H, d, J=7 Hz,CH arom), 7.20 (1H, t, J=7 Hz, CH arom.), 7.40 (4H, d, J=7 Hz, 4 CHarom.), 7.50 (4H, d, J=7 Hz, 4 CH arom.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 0.5 g ofmethyl(3-pyrrolidinylbenzyl)sulfone, 0.6 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 1.4 cm³ of a 1.6 Nsolution of n-butyllithium in hexane, 0.6 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3olis obtained in the form of a cream-colored solid.

EXAMPLE 68

On carrying out the operation according to the procedure of Example 58starting with 5.1 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidineand 17 cm³ of a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran, the residue obtained is purified by chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30cm) at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanolmixture (97/3 by volume) as eluent and collecting 100 cm³ fractions.Fractions 10 to 14 are combined, concentrated to dryness under reducedpressure (2.7 kPa). The yellow solid obtained is taken up in 2 cm³ ofdichloromethane and 10 cm³ of ethyl acetate and then filtered onsintered glass and washed with 2 cm³ of ethyl acetate. 1.6 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a white solid melting at 214° C. [NMRspectrum in DMSO-d6, T=300K, □ in ppm (400 MHz): 2.95 (3H, s, SCH₃),3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.50 (2H, d, J=5 Hz, OCH₂), 4.80(1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.30 (1H, d, J=7 Hz, CH arom.),between 7.35 and 7.45 (7H, m, 7CH arom.), 7.50 (4H, d, J=7 Hz, 4CHarom.)].

1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidinemay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 10.8 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol,2 cm³ of methanesulfonyl chloride and 8.5 g of 4-dimethylaminopyridine,the residue is purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 4 cm, height 40 cm) at a nitrogenpressure of 0.5 bar with dichloromethane as eluent and collecting 100cm³ fractions. Fractions 12 to 29 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). 5.2 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidineare obtained in the form of a gum.

1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]methylsulfonyl)methyl-(RS)}azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 5.8 g of[3-(tert-butylsilyloxymethyl)benzyl]methylsulfone and 5. g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 10.8 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-olare obtained in the form of a gum.

EXAMPLE 69

A mixture of 0.45 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidin,0.07 cm³ of 1-aminopiperidin in 4 cm³ of dimethylformamide is stirredfor 18 hours at room temperature. The mixture is taken up in 30 cm³ ofethyl acetate. The organic phase is washed with 3 times 50 cm³ of water,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). 0.2 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidineis obtained melting at 175° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (400 MHz): 1.40 (2H, m, CH₂), 1.60 (4H, m, 2CH₂), 2.85 (4H, m,2NCH₂), 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80(1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, m,2CH arom.), 9.45 (1H, s, NH)].

1[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidinemay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 29 starting with 2.6 g1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride, 0.9 g of pentafluorophenol, 0.9 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 25 cm³ ofdimethylformamide, the residue obtained is purified by chromatography ona silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height30 cm), at a nitrogen pressure of 0.5 bar with a mixture ofdichloromethane and ethanol (99/1 by volume) as eluent and collecting 30cm³ fractions. Fractions 7 to 12 are combined and concentrated todryness under reduced pressure (2.7 kPa). 0.9 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine is obtained inthe form of a foam.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: 2 cm³ of Jones reagent areadded to a mixture of 0.5 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidinein 9 cm³ of acetone, cooled to 5° C. This stirring is maintained for 2hours at this temperature and then 50 cm³ of a mixture of water and iceand 50 cm³ of ethyl acetate are added. The organic phase is decantedoff, washed with 50 cm³ of a saturated aqueous sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm), at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol as eluent and collecting 60 cm³fractions. Fractions 12 to 14 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). The solid obtained is crystallizedfrom 10 cm³ of ethyl ether. 32 mg of

1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a solid melting at 205° C. [NMR spectrum inDMSO-d6, T=300K, □ in ppm (400 MHz): 2.90 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.33 (4H, d, J=7 Hz, 4CHarom.), 7.39 (1H, d, J=7 Hz, CH arom.), 7.42 (4H, d, J=7 Hz, 4CH arom.),7.49 (1H, t, J=7 Hz, CH arom.), 7.57 (1H, d, J=7 Hz, CH arom.), 7.90(2H, s, CH arom. and NH⁺)].

EXAMPLE 70

On carrying out the operation according to the procedure for Example 4starting with 0.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methyl(RS)]azetidin-3-ol,0.24 g of methanesulfonyl chloride and 0.7 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 2 cm, height 18 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 50 cm³ fractions. Fractions 12 to 17 are combined,concentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is again purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), at a nitrogenpressure of 0.5 bar with dichloromethane as eluent and collecting 30 cm³fractions. Fractions 15 to 28 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). 0.25 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methylene]azetidineis obtained melting at 70° C. [NMR spectrum in DMSO-d6+CD₃CO₂D, T=300K,□ in ppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.80 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (4H, d,J=7 Hz, 4 CH arom.), 7.60 (2H, m, 2CH arom), 7.75 (2H, m, 2CH arom.)].

1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2 g ofmethyl(3-trifluoromethylsulfanylbenzyl)sulfone, 2.3 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.5 cm³ of a 1.6 Msolution of n-butyllithium in hexane, 0.9 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methyl-(RS)]azetidin-3-olis obtained in the form of a white solid.

Methyl(3-trifluoromethylsulfanylbenzyl)sulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 10 starting with 3-trifluoromethylsulfanylbenzylchloride and 3.2 g of sodium methanesulfinate, 5.2 g ofmethyl(3-trifluoromethylsulfanylbenzyl)sulfone are obtained in the formof a white solid melting at 125° C.

EXAMPLE 71

On carrying out the operation as in Example 38 (Method 1), starting with0.72 g of1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.18 cm³ of methanesulfonyl chloride and 0.66 g of4-dimethylaminopyridine, 0.42 g of1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 2.5 cm, height 15 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 25 cm³ fractions, in the form of a white foam [NMRspectrum in DMSO-d6, T=300K, □ in ppm (250 MHz): 3.05 (3H, s, SCH₃),3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.15 (6H, m,6CH arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.50 (4H, dd, J=6 and 8 Hz,4 CH arom.)].

1-[Bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: the operation is carried out asin Example 39 starting with 2.25 g of bis(4-fluorophenyl)bromomethane,1.1 g of potassium carbonate and 2.5 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride. After chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.4 cm, height 25 cm), at an argon pressureof 0.9 bar with a mixture of ethyl acetate and cyclohexane (2/8 byvolume) as eluent and collecting 60 cm³ fractions, fractions 23 to 39are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.72 g of1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained in the form of a white solid.

Bis(4-fluorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933)starting with 4 g of 4,4′-difluorobenzydrol, 2.70 cm³ of acetal bromideand 14 cm³ of a 33% hydrobromic acid solution in acetic acid.

EXAMPLE 72

On carrying out the operation as in Example 38 (Method 1), starting with1.22 g of1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.29 cm³ of methanesulfonyl chloride and 1.1 g of4-dimethylaminopyridine, 0.177 g of1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 23 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 60 cm³ fractions, in the form of a white foam [NMRspectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 3.05 (3H, s, SCH₃),3.95 (2H, s, NCH₂), 4.25 (2H, s, NCH₂), 5.35 (1H, s, NCH), 7.20 (6H, m,6CH arom.), 7.35 (3H, m, 3CH arom.), 7.55 (2H, m, 2CH arom.)].

1-[Bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: the operation is carried out asin Example 39 starting with 2 g of bis(2-fluorophenyl)bromomethane, 1.0g of potassium carbonate and 2.22 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride. After chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 3 cm, height 17 cm), at an argon pressure of1 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) aseluent and collecting 60 cm³ fractions, fractions 6 to 10 are combinedand then concentrated to dryness under reduced pressure (2.7 kPa). 1.22g of1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a whitish solid.

Bis(2-fluorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933),starting with 1.80 g of 2,2′-difluorobenzydrol, 1.22 cm³ of acetylbromide and 6.5 cm³ of a 33% solution of hydrobromic acid in aceticacid.

2,2′-difluorobenzydrol may be prepared according to the followingmethod: 32 cmof a 1.6 M solution of n-butyllithium in hexane are poureddropwise into a solution, cooled to −70° C. under argon, of 8.8 g of2-bromofluorobenzene in 100 cm³ of tetrahydrofuran. After stirring for10 minutes at −70° C., 2.1 cm³ of ethyl formate are added slowly andthen the mixture is stirred at −70° C. for 30 minutes. The reactionmedium is then brought to 0° C. and then supplemented with 50 cm³ ofethyl acetate and 100 cm³ of saturated ammonium chloride solution. Afterstirring, the organic phase is separated, dried over magnesium sulfate,concentrated to dryness at 55° C., under reduced pressure (2.7 Kpa).3.63 g of 2,2′-difluorobenzydrol are obtained in the form of a yellowoil.

EXAMPLE 73

On carrying out the operation as in Example 38 (Method 1), starting with1.5 g of1-bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.264 cm³ of methanesulfonyl chloride, and 0.98 g of4-dimethylaminopyridine, 0.55 g of1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 2.8 cm, height 25 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 60 cm³ fractions, in the form of a white solidmelting at 178° C. [NMR spectrum in DMSO-d6, T=300K, □ in ppm (250 MHz):3.05 (3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.25 (2H, s, NCH₂), 4.80 (1H, s,NCH), 7.10 (2H, m, 2CH arom.), 7.20 (2H, m, 2CH arom.), between 7.30 and7.50 (7H, m, 7CH arom.)].

1-[Bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be prepared in the following manner: on carrying out the operationaccording to Example 1 starting with 1.2 g of(3,5-difluorobenzyl)methylsulfone and 1.5 g of1-[bis(3-fluorophenyl)methyl]-azetidin-3-one, 1.95 g of1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained, after purification on a silica gel column (particle size0.06-0.200 mm, diameter 3.2 cm, height 30 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) aseluent and collecting 60 cm³ fractions, in the form of a white solidmelting at 170° C. (decomposition).

1-[Bis(3-fluorophenyl)methyl]azetidin-3-one may be prepared by carryingout the operation in a manner identical to the procedure described byKATRITZKY A. R. et al., J. Heterocycl. Chem., 271 (1994), starting with4.9 g of [bis(3-fluorophenyl)methyl]amine and 1.78 cm³ ofepichlorohydrin.

[Bis(3-fluorophenyl)methyl]amine may be prepared in the followingmanner: a solution of 5.17 g of 3,3′-difluorobenzophenone oxime in 30cm³ of tetrahydrofuran is poured, under an argon atmosphere over 30minutes, into a suspension of 1.27 g of lithium aluminum hydride in 80cm³ of tetrahydrofuran. After stirring for 5 hours under reflux, 1.3 cm³of water, 1.3 cm³ of 4 N sodium hydroxide, 2.6 cm³ of water and then 50cm³ of ethyl acetate are added successively. After drying over magnesiumsulfate and concentrating to dryness under reduced pressure (2.7 kPa),4.9 g of [bis(3-fluorophenyl)methyl]amine are obtained in the form of ayellow oil.

3,3′-Difluorobenzophenone oxime may be prepared according to thefollowing procedure: a solution of 1.6 g of hydroxylamine hydrochloridein 8 cm³ of water is poured dropwise into a solution of 5.0 g of3,3′-difluorobenzophenone in 10 cm³ of ethanol, and then 1.2 g of sodiumhydroxide pellets are added in small fractions. The reaction mixture,heated under reflux for 10 minutes, is cooled to 20° C. and thenacidified with 7.5 cm³ of 4 N hydrochloric acid. Once triturated, theoil precipitate obtained becomes a white solid which is filtered, washedwith water and then dried at 35° C. under reduced pressure (2.7 kPa).5.17 g of 3,3′-difluorobenzophenone oxime are obtained in the form of awhite solid.

EXAMPLE 74

On carrying out the operation as in Example 1, starting with 1.30 g of amixture of two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol,0.35 cm³ of methanesulfonyl chloride and 1.22 g of4-dimethylaminopyridine, 0.7 g of(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 2.4 cm, height 25 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (1/1 by volume) aseluent and collecting 30 cm³ fractions, in the form of a pinkish solid[NMR spectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 2.95 (3H, s,SCH₃), 3.95 (2H, m, NCH₂), 4.35 (2H, m, NCH₂), 5.25 (1H, s, NCH), 7.45(9H, m, 9CH arom.), 7.65 (1H, d, J=2 Hz, CH thiazole), 7.70 (1H, d, J=2Hz, CH thiazole)].

The mixture of the two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol,may be obtained in the following manner: on carrying out the operationas in Example 39 starting with 4.47 g of(RS)-bromo(4-chlorophenyl)(thiazol-2-yl)methane and 4.31 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride andafter chromatography on a silica gel column (particle size 0.06-0.200mm, diameter 5.6 cm, height 40 cm), at an argon pressure of 0.5 bar witha mixture of ethyl acetate and cyclohexane (25/75 by volume) up tofraction 35 and then with pure ethyl acetate as eluent and collecting 60cm³ fractions, fractions 38 to 40 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 1.3 g of the mixture of thetwo diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a whitish solid.

(RS)-bromo(4-chlorophenyl)(thiazol-2-yl)methane may be preparedaccording to the procedure described by BACHMANN W. E., J. Am. Chem.Soc., 2135 (1933), starting with 3.5 g of(RS)-(4-chlorophenyl)(2-thiazolyl)methanol, 3.81 g of acetyl bromide and12.0 cm³ of a 33% solution of hydrobromic acid in acetic acid.

(RS)-(4-chlorophenyl)(thiazol-2-yl)methanol may be prepared according tothe procedure described by G. EVAN BOSWELL et al., J. HeterocyclicChem., 32, 1801 (1995) starting with 4.22 g of 4-chlorobenzaldehyde and4.92 g of 2-bromothiazole.

EXAMPLE 75

On carrying out the operation as in Example 1, starting with 0.52 g of amixture of the two diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol,0.14 cm³ of methanesulfonyl chloride and 0.49 g of4-dimethylaminopyridine, 0.32 g of(RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 2.4 cm, height 20 cm), at an argon pressure of0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 byvolume) as eluent and collecting 30 cm³ fractions, in the form of awhite solid melting at 176° C. [NMR spectrum in DMSO-d6, T=300K, □ inppm (300 MHz): 2.98 (3H, s, SCH₃), 3.90 (2H, m, NCH₂), 4.20 (2H, s,NCH₂), 5.03 (1H, s, NCH), 6.85 (1H, dd, J=3 and 5 Hz, CH thiophene),7.08 (3H, m, 2CH arom. and 1CH thiophene), 7.22 (1H, t, J=8 Hz, CHarom.), 7.32 (3H, m, 2CH arom. and 1CH thiophene), 7.40 (2H, d, J=7 Hz,2CH arom.)].

The mixture of the two diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be prepared in the following manner: on carrying out the operationas in Example 1 starting with 1.60 cm³ of 1.6 N n-butyllithium insolution in hexane, 0.83 g of (3,5-difluorobenzyl)methylsulfone and 1.06g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-one, 0.55 gof the mixture of diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained, after purification on a silica gel column (particle size0.06-0.200 mm, diameter 2.8 cm, height 30 cm), at an argon pressure of0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 40 cm³ fractions, in the form of anoff-white solid.

1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-one may beprepared by carrying out the operation in the following manner: 3.04 cm³of dimethyl sulfoxide are poured over 10 minutes into a solution, cooledto −70° C., of 1.83 cm³ of oxalyl chloride in 20 cm³ of dichloromethaneunder argon. After stirring for 30 minutes at −60° C., a solution of 5.2g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-ol in 80 cm³of dichloromethane is poured in over 20 minutes, the mixture is stirredfor 3 hours at a temperature of between −60° C. and −70° C. and then9.12 cm³ of triethylamine are added. The mixture is then allowed toreturn to room temperature and then diluted with water. The organicphase is separated, dried over magnesium sulfate and then concentratedto dryness under reduced pressure. The residue is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 36cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (1/9 by volume) as eluent and collecting 60 cm³ fractions.3.3 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-one areobtained in the form of a yellow oil which crystallizes at roomtemperature.

1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-ol may beprepared in the following manner: 4.12 g of sodium bicarbonate are addedto a solution of 11.0 g of[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine in 80 cm³ of ethanol. Themixture is heated at 65° C. and supplemented with 4.03 cm³ ofepibromohydrin. After stirring for 20 hours at 65° C., the cooledmixture is filtered and the filtrate concentrated to dryness underreduced pressure (2.7 Kpa). The residue is chromatographed silica gelcolumn (particle size 0.06-0.200 mm, diameter 3.6 cm, height 32 cm), atan argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (25/75 by volume) as eluent and collecting 60 cm³ fractions.6.3 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-ol areobtained in the form of a pale yellow oil.

[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-amine may be prepared in thefollowing manner: a solution of 10.92 g of 2-thiophenecarbonitrile in 80cm³ of ethyl ether is poured slowly into a suspension, cooled to 10° C.,of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of4-bromochlorobenzene and 2.43 g of magnesium) in 120 cm³ of anhydrousethyl ether. After refluxing for one hour, the mixture is cooled to 10°C., supplemented slowly with 40 cm³ of methanol and then filtered onsupercel. 4.54 g of sodium borohydride are added under argon and insmall fractions over 15 minutes and then the reaction medium is stirredfor 20 hours at 20° C. The mixture obtained is diluted with ethylacetate and then washed with water. The organic phase is dried overmagnesium sulfate, concentrated to dryness at 50° C. under reducedpressure (2.7 kPa). The residue is chromatographed silica gel column(particle size 0.06-0.200 mm, diameter 5 cm, height 42 cm), at an argonpressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6by volume) as eluent and collecting 100 cm³ fractions. Fractions 6 to12, concentrated to dryness, correspond to 13 g of imine in the form ofa yellow oil which is taken up in 100 cm³ of methanol. The solutionobtained is supplemented with 2.4 g of sodium borohydride and stirredfor one hour at 5° C. The mixture obtained is diluted with ethyl acetateand then washed with water. The organic phase is dried over magnesiumsulfate, concentrated to dryness at 50° C. under reduced pressure (2.7Kpa). The residue is chromatographed silica gel column (particle size0.06-0.200 mm, diameter 3.2 cm, height 40 cm), at an argon pressure of0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume)as eluent and collecting 60 cm³ fractions, 11.0 g of[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine are obtained in the formof a yellow oil.

EXAMPLE 76

On carrying out the operation as described in Example 75, starting with1.66 g of the mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]-azetidin-3-ol,50 cm³ of dichloromethane, 0.45 cm³ of methanesulfonyl chloride, and1.64 g of 4-dimethylaminopyridine. 0.6 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of white crystals melting at 136° C., [a]²⁰_(D)=+3.2° (c=0.5% in dichloromethane).

The mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]-azetidin-3-olmay be prepared as described in Example 75, starting with 1.06 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one, 0.82 g of(3,5-difluorobenzyl)methylsulfone, 2.5 cm³ of 1.6 N solution ofn-butyllithium in hexane, and 25 cm³ of tetrahydrofuran. 1.7 g of themixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]-azetidin-3-olare obtained, after purification by chromatography, in the form of awhite solid.

(+)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-one may be preparedas described in Example 75, starting with 12.4 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol, 7.1 cm³ ofdimethyl sulfoxide, 4.4 cm³ of oxalyl chloride and 21.5 cm³ oftriethylamine. 9.2 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one are obtained inthe form of a pale yellow oil crystallizing at 20° C.

(+)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]-azetidin-3-ol may be preparedas described in Example 75, starting with 16.1 g of(+)-[(4-chlorophenyl)(thien-2-yl)methyl]amine, 130 cm³ of ethanol, 5.9cm³ of epibromohydrin and 6.05 g of sodium bicarbonate. 11.5 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol are obtained,after purification by chromatography, in the form of a cream-coloredoil.

(+)-4-[(Chlorophenyl)(thien-2-yl)methyl]amine may be prepared in thefollowing manner: 73 g of D-(−)-tartaric acid are added to a solution of109 g of [(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine in 500 cm³ ofmethanol. The mixture is concentrated to dryness under reduced pressure(2.7 kPa). The foam obtained is taken up in 2.05 liters of anethanol-water 90/10 by volume mixture. After stirring slowly for 20hours at 20° C., the crystalline suspension obtained is filtered, thecrystals washed with a minimum amount of the same mixture of solvents,and then dried. Another recrystallization is carried out under the sameconditions with 1.5 liters of the same mixture of solvents. 44.9 g ofcrystals of the acid tartrate of the amine are obtained. [a]²⁰_(D)=+10.3° (c=0.5% in dimethylformamide). This compound isrecrystallized from 600 cm³ of an ethanol-water 80/20 by volume mixture(the crystals are filtered and washed with twice 30 cm³ of the samemixture of solvents and then drained) and then recrystallized under thesame conditions with 400 cm³ of an ethanol-water 78/22 mixture. 28.2 gof acid D-(−)-tartrate of (+)-[(4-chlorophenyl)thien-2-yl)methyl]amineare obtained in the form of white crystals [a]²⁰ _(D)=+10.8° (c=0.5% indimethylformamide).

This salt is taken up in 400 cm³ of a 1 N aqueous solution of sodiumhydroxide and with 100 cm³ of ethyl acetate. The organic phase isseparated, washed with 100 cm³ of water, dried over magnesium sulfateand then concentrated to dryness under reduced pressure (2.7 kPa). 16.1g of (+)-[(4-chlorophenyl)-(thien-2-yl)methyl]amine are obtained in theform of an oil which crystallizes at 20° C. [a]²⁰ _(D)=+32.7° (c=0.5% indichloromethane).

EXAMPLE 77

On carrying out the operation as described in Example 75, starting with1.30 g of the mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]-azetidin-3-ol,40 cm³ of dichloromethane, 0.35 cm³ of methanesulfonyl chloride and 1.28g of 4-dimethylaminopyridine, 0.97 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of white crystals melting at 135° C. [a]²⁰_(D)=−3.4° (c=0.5% in dichloromethane).

The mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]-azetidin-3-olmay be prepared as described in Example 75, starting with 1.06 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one, 0.82 g of(3,5-difluorobenzyl)methylsulfone, 2.5 cm³ of 1.6 N solution ofn-butyllithium in hexane, and 25 cm³ of tetrahydrofuran. 1.3 g of themixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]-azetidin-3-olare obtained after purification by chromatography in the form of a whitesolid.

(−)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-one may be preparedas described in Example 75, starting with 11.4 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol, 200 cm³ ofdichloromethane, 4.0 cm³ of dimethyl sulfoxide, 4.0 cm³ of oxalylchloride and 19.5 cm³ of triethylamine, 8.3 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one are obtained inthe form of a pale yellow oil crystallizing at 20° C.

(−)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]-azetidin-3-ol may be preparedas described in Example 75, starting with 15.4 g of(−)-[(4-chlorophenyl)(thien-2-yl)methyl]amine, 120 cm³ of ethanol, 5.8cm³ of epibromohydrin and 5.8 g of sodium bicarbonate. 10.7 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol are obtained,after purification by chromatography, in the form of a cream-coloredoil.

(−)-4-[(Chlorophenyl)(thien-2-yl)methyl]amine may be prepared in thefollowing manner: 29 g of L-(+)-tartaric acid are added to a solution of43 g of [(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine in 200 cm³ ofmethanol. The mixture obtained crystallizes in 2 hours at roomtemperature. The crystals are filtered, washed with twice 10 cm³ ofmethanol. Recrystallization is carried out with 500 cm³ of anethanol-water 80/20 by volume mixture, the crystals are filtered, washedwith twice 30 cm³ of the same mixture of solvents and then dried undervacuum at 45° C. A final recrystallization is carried out with 350 cm³of an ethanol-water 78/22 by volume mixture, allowing the mixture to bestirred for 20 hours at 20° C. The crystals obtained are drained, driedunder reduced pressure (2.7 kPa). 26 g of acid L-(+)-tartrate of(−)-[(4-chlorophenyl)(thien-2-yl)methyl]amine are obtained. [a]²⁰_(D)=−10.7° (c=0.5% in dimethylformamide).

This salt is taken up in 400 cm³ of a 1 N aqueous sodium hydroxidesolution and with 100 cm³ of ethyl acetate. The organic phase isseparated, washed with 100 cm³ of water, dried over magnesium sulfateand then concentrated to dryness under reduced pressure (2.7 kPa). 15.4g of (−)-[(4-chlorophenyl)(thien-2-yl)methyl]amine are obtained in theform of an oil which crystallizes at 20° C. [a]²⁰ _(D)=˜31.7° (c=0.5% indichloromethane).

EXAMPLE 78

On carrying out the operation according to the procedure of Example 1starting with 3.4 g of1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS) azetidin-3-ol, 0.72cm³ of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine,1.9 g of 1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine areobtained, after recrystallization from 40 cm³ of acetonitrile, in theform of crystals melting at 210° C. [[NMR spectrum in DMSO-d6, T=300K, □in ppm (300 MHz): 1.15 (3H, t, J=6 Hz, CH₃), 2.92 (2H, q, J=6 Hz, Ch₂),3.83 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), between 7.20and 7.50 (15H, m, 3 phenyls)].

1-Benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]azetidin-ol may beobtained by carrying out the operation according to the proceduredescribed in Example 1 starting with 2.4 g of benzylethylsulfone, 2.2cm³ of diisopropylamine, 10 cm³ of 1.6 N n-butyllithium in solution inhexane, 65 cm³ of tetrahydrofuran and 3.1 g of1-benzhydrylazetidin-3-one. 3.6 g of1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol areobtained, after recrystallization from 30 cm³ of acetonitrile, in theform of white crystals melting at 222° C.

Benzylethylsulfone may be prepared by carrying out the operationaccording to the procedure of Example 2 starting with 6.3 g ofbenzylethylsulfide, 50 cm³ of acetic acid, 50 cm³ of water, 25 cm³ of 36N sulfuric acid and 24.8 g of oxone^(R). 3.2 g of benzylethylsulfone areobtained, by recrystallization from 20 cm³ of ethyl ether, in the formof a solid melting at 86° C.

Benzylethylsulfide may be prepared in the following manner: 1.2 g ofsodium hydride are added in small portions to a solution of 5 g ofbenzylmercaptan in 50 cm³ of dimethylformamide under argon, and then3.36 cm³ of ethyl iodide are poured in, while the temperature ismaintained below 45° C. The mixture is stirred for 2 hours and thentaken up in 200 cm³ of ethyl ether. The organic phase is washed with 200cm³ of water and then with 3 times 100 cm³ of water, dried overmagnesium sulfate and concentrated to dryness under reduced pressure(2.7 kPa). 6.3 g of benzylethylsulfide are obtained in the form of apale yellow liquid.

EXAMPLE 79

0.083 g of 1-amino-4-methylpiperazine is added to a solution of 0.45 gof1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidinein 5 cm³ dimethylformamide. The mixture is stirred for 20 hours at roomtemperature and then 40 cm³ of ethyl acetate are added. The organicphase is washed with 4 times 20 cm³ of water, dried over magnesiumsulfate and concentrated to dryness under reduced pressure (2.7 kPa).The residue is triturated with 10 cm³ of ethyl ether, filtered and thendried. 0.2 g of1-[(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[(N-4-methylpiperazinylcarbamoyl)phenyl]methylene}azetidineis obtained in the form of a yellow solid melting at 162° C. [NMRspectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 2.20 (3H, s, NCH₃),2.40 (4H, m, 2 NCH₂), 2.90 (4H, m, 2 NCH₂), 2.95 (3H, s, SCH₃), 3.80(2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.40 (4H, d, J=7Hz, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.), 7.55 (2H, m, 2CHarom.), 7.80 (2H, m, 2H, m, 2CH arom.), 9.50 (1H, s, CONH)].

1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidinemay be prepared in the following manner: 0.94 g ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.89 gof pentafluorophenol are added to a solution of 2.9 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinein 25 cm³ of dimethylformamide. The mixture is stirred for 20 hours atroom temperature and then taken up in 50 cm³ of ethyl acetate. Theorganic phase is washed with 100 cm³ of water, 200 cm³ of a saturatedaqueous sodium bicarbonate solution and then with twice 50 cm³ ofdistilled water, dried over magnesium sulfate and concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedsilica gel column (particle size 0.04-0.006 mm, diameter 2 cm), elutingwith a mixture of dichloromethane and ethanol (99/1 by volume). 0.92 gof1-[bis(4-chlorophenyl)methyl]-3-[(3-methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidineis obtained in the form of a white foam.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: a 36% solution of hydrochloricacid at a temperature of 50° C. is added to a solution of 3.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidinein 5 cm³ of acetic acid. The heating is continued for 48 hours and thenthe mixture is evaporated to dryness under reduced pressure (2.7 kPa).The residue is taken up in 30 cm³ of ethanol and again evaporated todryness. The residue is triturated in 35 cm³ of ethyl ether. 3.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a beige solid.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidinemay be prepared according to the procedure of Example 4, starting with11 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,150 cm³ of dichloromethane, 2.54 cm³ of methanesulfonyl chloride and10.7 g of 4-dimethylaminopyridine, at room temperature for 3 hours. Theresidue obtained is purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 4.5 cm) and eluted withdichloromethane and then with a mixture of dichloromethane and ethanol(99.6/0.4 by volume). The fractions are evaporated to dryness underreduced pressure (2.7 Kpa). 3.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a white foam.

1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be prepared in the following manner: a solution of 5 g of3-cyanobenzyl methyl sulfone in 500 cm³ of tetrahydrofuran is added over15 minutes to a solution of 17.6 cm³ of a 1.6 M n-butyllithium inhexane, in 30 cm³ of tetrahydrofuran under argon, and cooled to −70° C.The mixture is stirred for 1 hour 30 minutes. Next, a solution of 7.8 gof 1-[bis(4-chlorophenyl)methyl]-azetidin-3-one in 80 cm³ oftetrahydrofuran is poured in over 10 minutes. After stirring for 1 hour30 minutes, 60 cm³ of a saturated aqueous ammonium chloride solution arepoured in and then the mixture is allowed to return to room temperature.The mixture is taken up in 300 cm³ of ethyl acetate, the organic phasewashed with 200 cm³ of a saturated aqueous sodium chloride solution,dried over magnesium sulfate and evaporated under reduced pressure (2.7Kpa). 11 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

(3-Cyanobenzyl)methylsulfone may be prepared in the following manner:starting with a solution of 20.2 g of 3-chloromethylbenzonitrile in 200cm³ of ethanol, 17.4 g of 85% sodium methanesulfinate are added. Themixture is stirred for 20 hours under reflux and then taken up in 500cm³ of ethyl acetate and 500 cm³ of water. The insoluble matter isfiltered off, the organic phase in the filtrate is dried over magnesiumsulfate and evaporated to dryness under reduced pressure (2.7 Kpa). Thesolid obtained is triturated with 100 cm³ of ethyl ether. Afterfiltration and drying of the solid, 21 g of (3-cyanobenzyl)methylsulfoneare obtained in the form of white crystals melting at 165° C.

3-Chloromethylbenzonitrile may be prepared in the following manner: 32 gof 3-chloromethylbenzoamide in 200 cm³ of phosphorus oxychloride areheated at 95° C. for 3 hours, and then 1 liter of ice is loaded, themixture stirred for 1 hour and extracted with 500 cm³ ofdichloromethane. The organic phase is washed with 200 cm³ of water,dried over magnesium sulfate and evaporated to dryness under reducedpressure (2.7 Kpa). 20.2 g of 3-chloromethylbenzonitrile are obtained inthe form of a white solid.

3-Chloromethylbenzoamide may be prepared in the following manner: 150cm³ of a solution of ammonium hydroxide (d=0.90) are poured into asolution of 50 g of 3-chloromethylbenzoyl chloride in 150 cm³ of ethylether, the mixture is cooled, stirred for 1 hour, filtered and washedwith twice 200 cm³ of ethyl ether. 32 g of 3-chloromethylbenzoamide areobtained in the form of white crystals.

EXAMPLE 80

On carrying out the operation according to the procedure of Example 79starting with 0.5 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine0.06 cm³, 1,1′-dimethylhydrazine and 5 cm³ of dimethylformamide, 0.125 gof1-[bis(4-chlorophenyl)methyl]-3-{(3-(2,2′-dimethylcarbohydrazido)phenyl]methylsulfonyl)methylene}azetidineis obtained in the form of a white solid melting at 134° C. [NMRspectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 2.60 (6H, s, N(CH₃)₂),2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s,NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.),7.50 (2H, m, 2CH arom.), 7.80 (2H, m, 2CH arom.), 9.50 (1H, s, CONH)].

EXAMPLE 81

On carrying out the operation according the procedure described inExample 1 starting with 2.2 g of1-[bis(thien-2yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.64 cm³ of methanesulfonyl chloride, 2.3 g of 4-dimethylaminopyridineand 75 cm³ of dichloromethane, 1.3 g of1-[bis(thien-2yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained, after purification by chromatography and crystallizationfrom diisopropyl ether, in the form of white crystals melting at 165° C.[NMR spectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 3.00 (3H, s,SCH₃), 3.92 (2H, s, NCH₂), 4.28 (2H, s, NCH₂), 5.40 (1H, s, NCH), 6.95(2H, dd, J=5 and 2 Hz, 2CH thio.), 7.15 (2H, d, J=2 Hz, 2CH thio.), 7.20(2H, m, 2CH arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.50 (2H, d, J=5 Hz,2CH thio.)].

1-[Bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonylmethyl-(RS)]azetidin-3-olmay be obtained according to the procedure described in Example 1,starting with 1.5 g of 1-[bis(thien-2-yl)methyl]azetidin-3-one, 4 cm³ of1.6 N n-butyllithium in hexane, 1.3 g of1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained, after purification by chromatography, in the form of whitecrystals melting at 145° C.

1-[Bis-thien-2-yl)methyl]azetidin-3-one may be prepared by carrying outthe operation as described in Example 73, starting with 4 g of1-[bis(thien-2-yl)methyl]azetidin-3-ol, 2.6 cm³ of dimethyl sulfoxide,7.7 cm³ of triethylamine, 7.7 cm³ of oxalyl chloride, and 100 cm³ ofdichloromethane. The residue obtained is purified by chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30cm) with, as eluent, a mixture of cyclohexane/ethyl acetate (1/1 byvolume). The fractions obtained are evaporated to dryness under reducedpressure (2.7 Kpa). 3.2 g of 1-[bis(thien-2-yl)methyl]azetidin-3-one areobtained in the form of cream-colored crystals melting at 70° C.

1-[Bis(thien-2-yl)methyl]azetidin-3-ol may be prepared by carrying outthe operation as described in Example 73, starting with 6 g of1-bis(thien-2-yl)methyl]amine, 2.5 cm³ of epibromohydrin, 2.6 g ofsodium bicarbonate and 50 cm³ of ethanol. 4 g of1-[bis(thien-2-yl)methyl]azetidin-3-ol are obtained in the form of beigecrystals melting at 115° C.

1-[Bis(thien-2-yl)methyl]amine may be prepared in the following manner:a solution of 5 cm³ of thien-2-ylcarbonitrile in 50 cm³ of diethyl etheris poured dropwise into a suspension, cooled under argon to 10° C. ofthien-2-ylmagnesium bromide (prepared from 1.29 g of magnesium and 3.2cm³ 2-bromothiophene in 75 cm³ of diethyl ether). After refluxing for 1hour and 30 minutes, the reaction medium is cooled to 5° C. and then 20cm³ of methanol are poured in dropwise, the suspension filtered and thesolid washed with methanol. The filtrate obtained a brown solution. 2.45g of sodium borohydride are added to this solution, under argon, inseveral portions. The mixture is stirred at room temperature for 16hours and then diluted with ethyl acetate and supplemented with waterslowly. The organic phase is extracted, washed with water, dried overmagnesium sulfate and evaporated to dryness under reduced pressure (2.7kpa) at 55° C. A brown oil is obtained which is chromatographed on asilica gel column (particle size 0.2-0.063 mm, diameter 8 cm, height 25cm) and eluted with a mixture of cyclohexane/ethyl acetate (90/10 andthen 85/15 by volume). Fractions 21 to 30 are combined and evaporated todryness under reduced pressure (2.7 kpa). 11 g of1-[bis(thien-2-yl)methyl]amine are obtained in the form of acrystallized solid.

EXAMPLE 82

On carrying out the operation according to the procedure described inExample 1 starting with 0.47 g of 4-dimethylaminopyridine, 0.13 cm³ ofmethanesulfonyl chloride, 25 cm³ of dichloromethane and 0.48 g of1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol,0.25 g of1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methylene]azetidine isobtained, after purification by chromatography and crystallization fromdiisopropyl ether, in the form of a white solid [NMR spectrum inDMSO-d6, T=300K, □ in ppm (250 MHz): 2.23 (6H, s, PhCH₃), 2.98 (3H, s,SCH₃), 3.76 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 5.55 (1H, s, NCH), 7.10(4H, d, J=7 Hz, 4 CH arom.), 7.32 (4H, d, J=7 Hz, 4 CH arom.), 7.43 (5H,s, phenyl)].

1-(Bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olmay be prepared according to the procedure described in Example 39,starting with 0.59 g of bromo(bis-p-tolyl)methane, 20 cm³ ofacetonitrile, 0.3 g of potassium carbonate and 0.6 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride. Thereside obtained is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 4 cm, height 16 cm) with, as eluent, acyclohexane/ethyl acetate (7/3 by volume) mixture. The fractions areconcentrated to dryness under reduced pressure (2.7 Kpa). 0.48 g of1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olis obtained in the form of a white solid.

Bromo(di-p-tolyl)methane may be prepared according to the proceduredescribed by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).

3-[(Methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride maybe prepared according to the procedure described in Example 39 startingwith 7 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol,35 cm³ of dioxane. 35 cm³ of a 6.2 N solution of hydrochloric acid indioxane. 5 g of 3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olhydrochloride are obtained in the form of a white solid.

3-[(Methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olmay be prepared according to the procedure described in Example 38(Method 1), starting with 10 g of1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol, 600cm³ of dichloromethane and 2.52 cm³ of vinyl chloroformate. The residueis chromatographed on a silica gel column (particle size 0.06-0.2 mm,diameter 5.2 cm, height 36 mm with, as eluent, a cyclohexane/ethylacetate (7/3 by volume) mixture. The fractions are evaporated to drynessunder reduced pressure (2.7 Kpa). 7 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olare obtained in the form of a white solid.

EXAMPLE 83

A solution of 30 mg of sodium borohydride in 2 cm³ of methanol is pouredinto a solution of 0.77 g of(−)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 20 cm³ of methanol at 0° C. under argon. After stirring for 4 hoursat 0° C., water is added and the mixture is then extracted withdichloromethane. The organic phase is washed with a saturated aqueoussodium chloride solution, dried over magnesium sulfate and thenevaporated to dryness under reduced pressure (2.7 kpa). The white foamobtained is purified on a silica gel column (particle size 0.04-0.06 mm,diameter 3.2 cm, height 17 cm) with, as eluent, a cyclohexane/ethylacetate (60.40 by volume) mixture. 0.1 g of(+)-1-[(4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after crystallization from 1.5 cm³ of absolute ethanol, inthe form of white crystals melting at 190° C., [a]²⁰ _(D)=+4.2° (c=0.5%in methanol) [NMR spectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 3.05(3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.22 (2H, s, NCH₂), 4.48 (2H, d, J=6Hz, CH₂O), 4.75 (1H, s, NCH), 5.15 (1H, t, J=6 Hz, OH), 7.20 (2H, m, 2CHarom.), 7.28 (2H, d, J=7 Hz, 2CH arom.), 7.40 (5H, m, 5 CH arom.), 7.50(2H, d, J=7 Hz, 2CH arom.)].

(−)-1-[(4-Chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidinemay be prepared in the following manner: 3.32 cm³ of a 5 N solution ofhydrochloric acid are poured into a solution of 0.83 g of(+)-1-{4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 5 cm³ of tetrahydrofuran and then the mixture is kept stirring for 20hours. Dichloromethane and water are added to the reaction mediumfollowed by a 30% aqueous solution of sodium hydroxide until a pH=14 isobtained. The aqueous phase is extracted with dichloromethane, theorganic phase is washed successively with water, with a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate,filtered and evaporated to dryness under reduced pressure (2.7 kpa). 0.8g of(+)-1-[4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white foam.

(+)-1-{4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemay be obtained in the following manner: 0.93 g of1,8-Diazabicyclo[5-4-0]undec-7-ene is poured dropwise into a solution of2.42 g of the mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl-(R*)]azetidineand3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidinein 25 cm³ of tetrahydrofuran under argon at 0° C. After stirring for 1hour and 30 minutes at 0° C., the reaction medium is diluted with ethylacetate, washed with water and with a saturated aqueous sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand evaporated to dryness under reduced pressure. The crude product ispurified on a silica gel column (particle size 0.04-0.06 mm, diameter4.8 cm, height 17.5 cm) with, as eluent, a cyclohexane/ethyl acetate(80/20 by volume) mixture. 1.21 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a yellow foam.

The mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidineand3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidinemay be prepared in the following manner: 3.27 cm³ of n-butyllithium arepoured dropwise into a solution of 1.08 g of 3-5-difluorobenzyl methylsulfone under argon, cooled to −70° C., and then the mixture is keptstirring for 1 hour at −70° C. and then a solution of 1.80 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-onein 10 cm³ of tetrahydrofuran is poured in dropwise. After stirring for 3hours at −70° C. and for 1 hour at −20° C., a solution of 0.74 cm³ ofacetyl chloride in 10 cm³ of anhydrous diethyl ether at −20° C. ispoured in and the mixture is stirred for 2 hours at −20° C. The reactionmedium is thrown over water, the mixture is extracted with ethylacetate, the organic phase washed with water and with a saturatedaqueous sodium chloride solution, dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kpa). 2.42 g of themixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidineand3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidineare obtained in the form of a yellow oil.

(+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-onemay be prepared in the following manner: 2.24 cm³ of triethylamine arepoured into a solution of 1.38 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-olin 20 cm³ of anhydrous dimethyl sulfoxide under argon, followed dropwiseby 1.65 g of a solution of sulfur trioxide pyridine complex in 20 cm³ ofanhydrous dimethyl sulfoxide. After stirring for 1 hour and 15 minutesat room temperature, the reaction medium is thrown over ice, extractedwith ethyl acetate, the organic phase washed with water, with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kpa). The oily residue obtained (1.31 g), combined with anotherbatch of the same crude compound (1.21 g), are purified together on asilica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height18 cm), with, as eluent, a cyclohexane/ethyl acetate (80/20 by volume)mixture. 1.87 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-oneare obtained in the form of a yellow oil. [a]²⁰365 nm=±5.9° (c=0.5;methanol).

(+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-olmay be described according to the procedure described in Example 73,starting with 4.43 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine, 40 cm³of absolute ethanol, 1.25 cm³ of epibromohydrin and 1.28 g of sodiumbicarbonate. 1.66 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-olare obtained in the form of a yellow oil.

Chiral (+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}aminemay be obtained in the following manner: 3.95 cm³ of ethylene glycol arepoured into a suspension of 18.16 g of chiral(R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochloride, in1000 cm³ of toluene, and 0.82 g of para-toluenesulfonic acid monohydrateis added. After stirring for 20 hours at the reflux temperature, thereaction medium is cooled, washed with a saturated aqueous sodiumbicarbonate solution, with water and with a saturated aqueous sodiumchloride solution. The organic phase is dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure. The residueobtained is purified on a silica gel column (particle size 0.04-0.06 mm,diameter 8.4 cm, height 21.5 cm) with, as eluent, a cyclohexane/ethylacetate (30/70 by volume) mixture, collecting 250 cm³ fractions.Fractions 23 to 30 are concentrated to dryness under reduced pressure(2.7 kpa). 1.39 of chiral(+)-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine areobtained in the form of a yellow oil.

Chiral (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochloridemay be prepared in the following manner: 330 cm³ of methanol are pouredinto a solution of 51.4 g of the diastereoisomerN-{(4-chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)}-(R)-2-phenylglycinolin 660 cm³ of anhydrous dichloromethane, the mixture cooled with an icebath, 60.96 g of lead tetraacetate added, the mixture stirred for 5minutes and then 1 liter of a phosphate buffer solution pH 7 poured in.After stirring for 30 minutes at room temperature, the mixture isfiltered and the aqueous phase is extracted with dichloromethane. Theorganic phase is concentrated to dryness under reduced pressure (2.7kpa). The residue is taken up in 1 liter of diethyl ether andsupplemented with 1 liter of a 3 N aqueous solution of hydrochloricacid, the mixture is stirred for 15 minutes at room temperature, theaqueous phase is separated, washed with ethyl acetate and thenconcentrated to dryness under reduced pressure (2.7 kpa). 18.16 g ofchiral (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochlorideare obtained in the form of a white solid.

N-{(4-chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)}-(R)-2-phenylglycinolmay be prepared in the following manner: 286 cm³ of 1.6 M n-butyllithiumin hexane are poured dropwise into a solution, cooled to −70° C., underargon, of 87.7 g of 4-bromochlorobenzene and the mixture is stirred for15 minutes at −70° C. This solution obtained is then added dropwise tothe following solution cooled to 0° C.: 30 g of(R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglycinol in 300 cm³ ofdiethyl ether. The mixture is stirred for 2 hours at 0° C. and thenthrown over water. The organic phase is washed with water and then witha saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kpa). 71.5 g of a reddish oil are obtained, which oil is purifiedon a silica gel column (particle size 0.04-0.06 mm, diameter 11 cm,height 45 cm), with, as eluent, a cyclohexane/ethyl acetate (85/15 byvolume, then 80/20 and 75/25) mixture, collecting 1 liter fractions.Fractions 11 to 17 are concentrated to dryness under reduced pressure(2.7 kpa). 39.85 g of the sole diastereoisomerN-{4-(chlorophenyl)-[4-diethoxymethyl)phenyl]methyl-(R*)}-(RS)-2-phenylglycinolare obtained in the form of an orange red oil.

(R)-N-[4-diethoxymethyl)benzylidene]-2-phenylglucinol may be prepared inthe following manner: 35.9 cm³ of 4-(diethoxymethyl)benzaldehyde arepoured into a white suspension of 24.7 g of (R)-(−)-2-phenylglucinol in500 cm³ of toluene. The cloudy yellow solution is heated under refluxfor 6 hours 30 minutes, and is then stirred at room temperature for 20hours. After concentrating the reaction medium to dryness under reducedpressure (2.7 kpa), 61.6 g of(RS)-N-[4-diethoxymethyl)benzylidene]-2-phenylglucinol are obtained inthe form of a yellow oil.

EXAMPLE 84

On carrying out the operation according to the procedure of Example 1,but starting with 5.6 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol,100 cm³ of dichloromethane, 1.59 g of methanesulfonyl chloride and 4.5 gof 4-dimethylaminopyridine. The mixture is kept stirring for 3 hours atroom temperature. The crude product obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm and weight of silica 250 g), eluting at a nitrogenpressure of 0.5 bar with an ethyl acetate/cyclohexane (30/70 by volume)mixture and collecting 100 cm³ fractions. Fractions 12 to 18 arecombined, concentrated to dryness under reduced pressure (2.7 kpa). 3.2g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxy-carbonyl-N-methylamino)phenyl](methylsulfonyl)-methylene}azetidineare obtained in the form of a white foam [NMR spectrum in DMSO-d6,T=300K, □ in ppm (300 MHz): 1.30 (9H, s, OC(CH₃)₃), 2.65 (3H, s, J=6 Hz,NCH₃), 2.85 (3H, s, SCH₃), 3.50 (2H, s, NCH₂), 3.90 (2H, s, NCH₂), 4.45(1H, s, NCH) between 6.85 and 7.05 (8H, m, 8 CH arom.), 7.10 (4H, d, J=7Hz, 4 CH arom.)].

1-[Bis(4-chlorophenyl)methyl]-3-{[3-N-tertbutyloxycarbonyl-N-methylamino)phenyl]methylsulfonyl)methyl-(RS)}azetidin-3-olmay be prepared according to the procedure described in Example 1starting with 3.8 g of[3-(N-tertbutyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 50 cm³ oftetrahyrofuran, 9.5 cm³ of a 1.6 N solution of n-butyllithium in hexane,3.82 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one. The crude productis purified by chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 4 cm, weight of silica 250 g), eluting at anitrogen pressure of 0.5 bar with dichloromethane and then with adichloromethane and ethanol mixture (99/1 by volume) and collecting 500cm³ fractions. Fractions 10 to 16 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). 5.6 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(n-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol,are obtained in the form of a foam.

EXAMPLE 85

2.7 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidineazetidine in 30 cm³ of diozane and 30 cm³ of a 4.7 N solution ofhydrochloric dioxane are stirred for 20 hours. The reaction medium isevaporated to dryness under reduced pressure (2.7 kpa), taken up in 50cm³ of water and 50 cm³ of ethyl acetate, stirred and neutralizedcarefully with a saturated aqueous sodium bicarbonate solution. Theorganic phase is separated, dried over magnesium sulfate, treated withanimal charcoal and then concentrated under reduced pressure (2.7 kpa)to a volume of about 25 cm³, then filtered, concentrated to drynessunder reduced pressure. 1.3 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of white crystals melting at 228° C. [NMRspectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 2.65 (3H, s, J=6 Hz,NCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80(1H, s, NCH), 5.85 (1H, q, J=6 Hz, NH), 6.55 (3H, m, 3 CH arom.), 7.15(1H, t, J=7 Hz, CH arom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 7.50 (4H, m,4CH arom.)].

EXAMPLE 86

On carrying out the operation as in Example 1, starting with 0.40 g of amixture of two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.10 cm³ of methanesulfonyl chloride and 0.37 g of4-dimethylaminopyridine, 0.13 g of(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 1.2 cm, height 20 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (40/60 by volume) aseluent and collecting 20 cm³ fractions, in the form of a pinkish solid[NMR spectrum in DMSO-d6, T=300K, □ in ppm (300 MHz): 3.05 (3H, s,SCH₃), 4.05 (2H, s, NCH₂), 4.35 (2H, m, NCH₂), 5.25 (1H, s, NCH), 7.20(2H, d, J=8 Hz, 2CH arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.45 (2H, d,J=7 Hz, 2CH arom.), 7.50 (2H, d, J=7 Hz, 2CH arom.), 7.70 (1H, d, J=2Hz, CH thiazole), 7.75 (1H, d, J=2 Hz, CH thiazole)].

The mixture of the two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationas in Example 72, starting with 1.01 g of(RS)-bromo(4-chlorophenyl)thiazol-2-ylmethane and 0.55 g of(RS)-3-[3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.06-0.200 mm, diameter 4.4 cm, height 38 cm), at an argon pressureof 0.5 bar and eluting with a mixture of ethyl acetate and cyclohexane(30/70 by volume and then 40/60 from fraction 16) and collecting 60 cm³fractions, fractions 21 to 35 are combined and concentrated to drynessunder reduced pressure (2.7 kPa). 0.4 g of the mixture of the twodiastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methyl-sulfonyl)methyl-(RS)]azetidin-3-olwhich is obtained in the form of a whitish solid.

EXAMPLE 87

50 cm³ of pyrrolidine are added to a solution of 0.32 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, and 5 mg of sodium iodide in 10 cm³ of dichloromethane.After stirring for 20 hours at 20° C., 50 mm³ of pyrrolidine are addedto the mixture, stirred for 8 hours and then 50 mm³ of pyrrolidine areagain added and the mixture is stirred for 20 hours at 20° C. Thereaction mixture is washed with water and then the organic phase isdried over magnesium sulfate and concentrated to dryness under vacuum(2.7 kPa). The residue obtained is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), atan argon pressure of 0.1 bar, eluting with dichloromethane and then witha dichloromethane and methanol mixture (97.5/2.5 by volume) andcollecting 3 cm³ fractions. Fractions 12 to 40 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of1-{(R*)-(4-chlorophenyl)[4-pyrrolidinylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-ene]azetidine,form A isomer, is obtained in the form of a white foam [a]²⁰365nm=˜22.5°±0.7 (c=0.5%; dichloromethane) [¹H NMR spectrum (300 MHz,CDCl₃, □ in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 (s, 3H), 3.58 (s,2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

1-{(R*)-[4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, may be prepared by carrying out the operation in thefollowing manner: 12.4 cm³ of methanesulfonyl chloride are added to asolution of 28.0 g of the mixture of the 2 diastereoisomers (forms A)1-{(R*)-[(4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-oland1-{(R*)-[4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-oland 32 g of 4-dimethylaminopyridine, in 500 cm³ of dichloromethane.After stirring for 1 hour at 10° C. and then 1 hour at 20° C., thereaction mixture is washed with 500 cm³ of water, the organic phase isdried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 6 cm, height 30 cm), at anargon pressure of 0.2 bar, eluting with dichloromethane and collecting250 cm³ fractions. Fractions 9 to 25 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 6.3 g of1-{(R*)-[4-chloromethyl)-phenyl](4-chlorophenyl)methyl}-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, are obtained in the form of a white foam.

The mixture of the 2 diastereoisomers (forms A)1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol,and1-{(R*)-[(4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,may be prepared by carrying out the operation in the following manner:60 mm³ of thionyl chloride are added to a solution of 0.20 g of themixture of the 2 diastereoisomers (forms A)1-{(R*)-[4-(chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,in 10 cm³ of dichloromethane. After stirring for 20 hours at 20° C., 5cm³ of a saturated aqueous sodium hydrogen carbonate solution are addedto the reaction mixture an then the mixture is stirred for 15 minutes.The mixture is separated after settling out, the organic phase is washedwith water, dried over magnesium sulfate and then concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 1.0 cm,height 20 cm), at an argon pressure of 0.2 bar, eluting with acyclohexane and ethyl acetate mixture (75/25 by volume) and collecting20 cm³ fractions. Fractions 4 to 7 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 0.17 g of the mixture of the 2diastereoisomers (forms A)1-{(R*)-[4-(chloromethyl)phenyl]-[4-chlorophenyl)]methyl}-3[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3[(S)(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-olis obtained in the form of a white foam.

The mixture of the 2 diastereoisomers (forms A)1{(R*)-4-(chlorophenyl)phenyl][4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and1-{(R*)-(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol,may be prepared by carrying out the operation in the following manner:1.6 cm³ of a 1.5 M solution of diisobutylaluminum hydride in toluene areadded to a solution, maintained under argon and cooled to −30° C., of0.58 g of the mixture of the 2 diastereoisomers (forms A)3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand3-acetoxy-1-[(R*)-(4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]-azetidine,in 10 cm³ of anhydrous toluene. After stirring for 15 minutes at −30°C., 1.0 cm³ of this same hydride solution is again added and then themixture is allowed to return to 0° C. After stirring for 30 minutes, thestirred mixture is supplemented with 3 cm³ of water and 6 cm³ of 1 Nsodium hydroxide and then extracted with 25 cm³ of dichloromethane. Theorganic phase is washed with 5 cm³ of water, 5 cm³ of brine, and thendried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), atan argon pressure of 0.1 bar, eluting with a cyclohexane and ethylacetate mixture (50/50 by volume) and collecting 30 cm³ fractions.Fractions 4 to 12 are combined and then concentrated to dryness underreduced pressure (2.7 kPa). 0.42 g of the mixture of the 2diastereoisomers (forms A)1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-olis obtained in the form of a white lacquer.

The mixture of the 2 diastereoisomers (forms A)3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)}azetidineand3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)}azetidinemay be prepared by carrying out the operation as described in Example40, starting with 1.0 g of (3,5-difluorobenzyl)methylsulfone, 30 cm³ oftetrahydrofuran, 3 cm³ of a 1.6 N solution of n-butyllithium in hexane,1.45 g of1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one,form A isomer, and 0.43 g of acetyl chloride. 1.28 g of the mixture ofthe 2 diastereoisomers (forms A)3-acetoxy-1-[(R*)-(4-chlorophenyl)[4-methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand3-acetoxy-1-[(R*)-(4-chlorophenyl)[4-methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineare obtained in the form of a beige foam.

1-{(R*)-[(4-chlorophenyl)[4-methoxycarbonyl)phenyl]methyl}-3-one, form Aisomer, may be prepared by carrying out the operation as described inExample 40, starting with 0.55 cm³ of oxalyl chloride, 25 cm³ ofdichloromethane, 0.90 cm³ of dimethyl sulfoxide, 1.75 g of1-{(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, and2.70 cm³ of triethylamine. 1.45 g of1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one,form A isomer, are obtained in the form of a yellow foam.

1-{(R*)(4-chlorophenyl)[4-methoxycarbonyl)phenyl]methyl}-azetidin-3-ol,form A isomer, may be prepared by carrying out the operation accordingto the procedure described by KATRITZKY A. R. et al., in J. Heterocycl.Chem., (1994), 271 from 2.0 g ofmethyl(+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate, 30 cm³ ofethanol, 0.60 g of sodium hydrogen carbonate and 0.60 cm³ ofepibromhydrin. 1.76 g of1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-azetidin-3-ol,form A isomer, are obtained in the form of a pasty solid.

Methyl(+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate may be preparedby carrying out the operation in the following manner: 2.51 g ofD-(−)-tartaric acid are added to a solution of 9.2 g ofmethyl(4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate in 10 cm³ ofmethanol. The solution is concentrated to dryness under reduced pressure(2.7 kPa). The cream-colored foam obtained is dissolved in 50 cm³ ofethanol containing 5% water and the resulting solution is allowed tocrystallize for 20 hours at 20° C. The crystals are filtered, washedwith ethanol containing 5% water, drained and then dried under reducedpressure (2.7 kPa). 3.4 g of white crystals are obtained which arecalled “A crystals” [and which are stored for the subsequent preparationof the second enantiomer,methyl(−)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate]. The motherliquors are concentrated to dryness and a white foam (8.1 g) is obtainedwhich is dissolved in 100 cm³ of ethyl acetate. The solution obtained issupplemented with 50 cm³ of 1 N sodium hydroxide, stirred and separatedafter settling out. The organic phase is washed with 50 cm³ of water andthen dried over magnesium sulfate and concentrated to dryness underreduced pressure (2.7 kPa). A yellow solid is obtained which isdissolved in 100 cm³ of methanol. The solution obtained is supplementedwith 1.85 g of L-(+)-tartaric acid and the resulting solution isconcentrated to dryness under reduced pressure (2.7 kPa). Acream-colored foam is obtained which, once dissolved in 27 cm³ ofethanol containing 4% water, is allowed to crystallize for 20 hours at20° C. The crystals are filtered, washed with ethanol containing 4%water, drained and then dried under reduced pressure (2.7 kPa). 3.4 g ofmethyl(+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate L-(+)-tartratecrystals are obtained which are recrystallized from 60 cm³ of ethanolcontaining 5% water. After draining and then drying, 2.78 g of whitecrystals are obtained which are dissolved in 50 cm³ of water and thendried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). 2.1 g ofmethyl(+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate are obtained inthe form of a white solid.

Methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate may be prepared bycarrying out the operation in the following manner: 3.9 cm³ of hydrazinehydrate are added to a suspension of 16.3 g of methyl4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate in 200 cm³ ofmethanol. After stirring for 5 hours at the reflux temperature and thenfor 20 hours at 20° C., the reaction mixture is filtered and thefiltrate is concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is taken up in a mixture of 200 cm³ of water and200 cm³ of ethyl acetate. After stirring for 15 minutes, the resultingsuspension is filtered, the filtrate separated after settling out in aseparating funnel, and the organic phase is washed with 50 cm³ of water,dried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). 8.4 g of methyl4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate are obtained in the formof a pale yellow oil.

Methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate may beprepared by carrying out the operation in the following manner: 12.6 gpotassium phthalimide are added to a solution of 11.6 g of methyl4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate in 70 cm³ ofdimethylformamide. After stirring for 3 hours at the reflux temperature,the reaction mixture is cooled to 20° C. and then supplemented with 300cm³ of ethyl acetate and 300 cm³ of water. After stirring, the mixtureis separated after settling out, the aqueous phase reextracted withtwice 100 cm³ of ethyl acetate, the combined organic phases are washedwith twice 400 cm³ of water and then dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). 16.3 g ofmethyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate are obtainedin the form of a pasty yellow solid.

Methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate may be prepared bycarrying out the operation in the following manner: 10.18 g ofN,M′-carbonyldiimidazole and 54.3 cm³ of allyl bromide are added to asolution of 17.4 g of methyl4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate in 200 cm³ ofacetonitrile. After stirring for 30 minutes at 20° C., the reactionmixture is heated under reflux for 2 hours, stirred for 20 hours at 20°C. and concentrated to dryness under reduced pressure (2.7 kPa). Themixture, taken up in dichloromethane, is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm), at anargon pressure of 0.5 bar, eluting with dichloromethane and collecting500 cm³ fractions. Fractions 3 to 6 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 11.6 g of methyl4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate are obtained in the formof an oil which will be used as it is in the next step.

Methyl 4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate may be preparedby carrying out the operation in the following manner: 1.21 g of sodiumborohydride are slowly added in small fractions to a suspension of 2.75g of methyl 4-(4-chlorobenzoyl)benzoate in 200 cm³ of methanol at 20° C.(heating of the medium up to 50° C. occurs). After stirring for 20 hoursat 20° C., the reaction mixture is concentrated to a reduced volume andthen supplemented with 150 cm³ of dichloromethane and, while stirring,with 100 cm³ of 0.5 N hydrochloric acid. After separating after settlingout, the organic phase is dried over magnesium sulfate and concentratedto dryness under reduced pressure (2.7 kPa). 2.5 g of methyl4-[(RS)-(4-chlorophenyl)-(hydroxy)methyl]benzoate are obtained in theform of a colorless oil which slowly crystallizes at 20° C., and whichwill be used as it is in the next step.

Methyl 4-(4-chlorobenzoyl)benzoate may be prepared by carrying out theoperation in the following manner: 27.4 cm³ of tri-n-butylphosphine areadded, under argon, to a solution, cooled to −22° C., of 19.3 g ofterephthalic acid chloride monomethyl ester in 200 cm³ oftetrahydrofuran. After stirring for 20 minutes at −22° C., a solution of4-chlorophenyl]magnesium bromide (prepared from 19.15 g of4-bromochlorobenzene, 2.43 g of magnesium and an iodine crystal in 100cm³ of diethyl ether under reflux) is poured in while this temperatureis maintained. After stirring for 30 minutes at −22° C., 150 cm³ of 1 Nhydrochloric acid are slowly added, the mixture is allowed to return to20° C. and then the medium is diluted with 200 cm³ of diethyl ether. Thewhite suspension obtained is filtered, the solid is washed with twice 50cm³ of water and then with twice 50 cm³ of diethyl ether. 16.2 g ofmethyl 4-(4-chlorobenzoyl)benzoate are obtained, after draining and thendrying under reduced pressure (2.7 kPa), in the form of a white solidmelting at 170° C.

EXAMPLE 88

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.025 g of3,3-dimethylpiperidine. The crude product is chromatographed on a silicagel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and then eluting with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 8 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.040 g of1-{(R*)-[4-(chlorophenyl)[4-(3,3-dimethylpiperadin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 0.94 (s, 6H), 1.21 (mt, 2H), from 1.50 to1.65 (mt, 2H), 1.99 (broad s, 2H), 2.27 (unresolved complex, 2H), 2.81(s, 3H), 3.36 (s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84(tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 89

The operation is carried out as described in Example 87, starting with0.05 g of methylsulfonyl methyl1-{(R*)-[4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.025 g of thiomorpholine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/15 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.038 g of1-{(R*)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(30 MHz, CDCl₃, □ in ppm): from 2.60 to 2.75 (mt, 8H), 2.80 (s, 3H),3.44 (s, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz,1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 90

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.025 g ofN-cyclohexyl-N-ethylamine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and ethanol mixture (95/5 by volume), collecting 2.5 cm³fractions immediately after using this element mixture. 0.22 g of1-{(R*)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]-methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,form A isomer, is obtained in the form of a white foam ]¹H NMR spectrum(300 MHz, CDCl₃ with addition of a few drops of CD₃COOD-d4, □ in ppm):from 1.15 to 1.25 (mt, 2H), 1.29 (t, J=7.5 Hz, 3H), from 1.45 to 1.65(mt, 4H), 1.88 (mt, 2H), 2.17 (mt, 2H), 2.81 (s, 3H), 3.05 (q, J=7.5 Hz,2H), 3.27 (mt, 1H), 3.95 (mt, 2H), 4.18 (s, 2H), 4.40 (mt, 2H), 4.66 (s,1H), 6.82 (tt, J=8.5 and 2.5 Hz, 1H), 7.00 (mt, 2H), from 7.20 to 7.40(mt, 4H), 7.41 (d, J=8 Hz, 2H), 7.53 (d, =8 Hz, 2H)].

EXAMPLE 91

The procedure is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.032 g of4-(ethoxycarbonyl)piperazine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 8 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.021 g of1-{{(R*)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, □ in ppm): 1.25 (t, J=7 Hz, 3H), 2.36 (mt, 4H), 2.80(s, 3H), 3.44 (s, 2H), 3.46 (mt, 4H), 3.85 (mt, 2H), 4.13 (q, J=7 Hz,2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98(mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 92

The operation is carried out as described in Example 87, starting with0.05 g1-{(R*)-[4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.023 g ofN-cyclopropyl-N-propylamine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 9 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.026 g of1-{(R*)-(4-chlorophenyl)[(4-N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃ with addition to a few drops of CD₃COOD-d4, □ in ppm):0.34 (mt, 2H), 0.70 (mt, 2H), 0.91 (t, J=7 Hz, 3H), 1.08 (mt, 1H), 1.76(mt, 2H), 2.82 (s, 3H), 2.92 (d, J=7 Hz, 2H), 3.00 (mt, 2H), 3.90 (mt,2H), 4.25 (s, 2H), 4.37 (mt, 2H), 4.59 (s, 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 7.00 (mt, 2H), from 7.20 to 7.45 (mt, 8H)].

EXAMPLE 93

The operation is carried out as described in Example 87, but by stirringthe reaction mixture for 6 days at 20° C., starting with 0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer. 1.0 cm³ of dichloromethane, 5 mg of sodium iodide and0.020 g of diisopropylamine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 8 are combined and then concentrated to dryness under reducedpressure (2.7 ka). 0.028 g of1-{(R*)-(4-(chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 1.00 (unresolved complex, 12H), 2.80 (s,3H), from 2.90 to 3.10 (unresolved complex, 2H), 3.58 (mt, 2H), 3.84(mt, 2H), 4.33 (mt, 2H), 4.48 (s, 1H), 6.82 (tt, J=8.5 and 2.5 Hz, 1H),6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 94

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.027 g ofbis(2-methoxyethyl)amine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 10 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.014 g of1-{{(R*)-(4-chlorophenyl){4-[bis(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 2.70 (broad t, J=5.5 Hz, 4H), 2.81 (s, 3H),3.29 (s, 6H), 3.46 (broad t, J=5.5 Hz, 4H) 3.65 (broad s, 2H), 3.85 (mt,2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98(mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 95

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.020 g ofdi-n-propylamine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 2.5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 8 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.025 g of1-{(R*)-(4-(chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, □ in ppm): 0.85 (t, J=7 Hz, 6H) 1.45 (mt, 4H), 2.34 (t,J=7.5 Hz, 4H), 2.80 (s, 3H), 3.48 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H),4.50 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to7.40 (mt, 8)].

EXAMPLE 96

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.017 g of piperidine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 5 to 10 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.035 g of1-{(R*)-(4-(chlorophenyl)[4-(piperadin-1-ylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-ene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): from 1.35 to 1.65 (mt, 6H), 2.35 (unresolvedcomplex, 4H), 2.80 (s, 3H), 3.41 (broad s, 2H), 3.84 (mt, 2H), 4.33 (mt,2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from7.20 to 7.40 (mt, 8H)].

EXAMPLE 97

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.020 g ofN-methylpiperazine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and ten with a dichloromethaneand methanol mixture (95/5 by volume), collecting 2.5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 9 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.025 g of1-{(R*)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 2.28 (s, 3H), from 2.30 to 2.60 (unresolvedcomplex, 8H), 2.80 (s, 3H), 3.5 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H),4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20to 7.40 (mt, 8H)].

EXAMPLE 98

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.018 g of morpholine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.0222 g of1-{(R*)-[4-(chlorophenyl)[4-(morpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 2.41 (t, J=5 Hz, 4H), 2.80 (s, 3H), 3.43 (s,2H), 3.69 (t, J=5 Hz, 4H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H),6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt,8H)].

EXAMPLE 99

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.020 cm³ of D-prolinol.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.025 g of1-{(R*)-(4-chlorophenyl)[4-((2R)-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, (CD₃)₂SO-d6 with addition of a few drops of CD₃COOD-d4, □ inppm): from 1.60 to 2.15 (mt, 4H), from 2.90 to 3.05 (mt, 1H), 2.98 (s,3H), 3.13 (mt, 1H), 3.38 (mt, 1H), from 3.50 to 3.60 (mt, 1H), 3.56 (d,J=5 Hz, 2H), 3.90 (mt, 2H), 4.04 (d, J=13.5 Hz, 2H), 4.21 (mt, 2H), 4.40(d, J=13.5 Hz, 2H), 4.78 (s, 1H), 7.14 (mt, 2H), 7.27 (tt, J=9 and 2.5Hz, 1H), from 7.30 to 7.55 (mt, 8H)].

EXAMPLE 100

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.015 g of diethylamine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 4 to 9 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.025 g of1-{(R*)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, □ in ppm): 1.03 (t, J=7 Hz, 6H), 2.50 (q, J=7 Hz, 4H),2.81 (s, 3H), 3.50 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.49 (s, 1H),6.84 (tt, J=9 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt,8H)].

EXAMPLE 101

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ dichloromethane, and 0.026 g ofN-(hydroxyethyl)piperazine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 10 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.032 g of1-{{(R*)-[4-(chlorophenyl){4-[4-(hydroxyethyl)piperazin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): from 2.40 to 2.60 (mt, 8H), 2.54 (t, J=5.5Hz, 2H), 2.80 (s, 3H), 3.44 (s, 2H), 3.60 (t, J=5.5 Hz, 2H), 3.84 (mt,2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98(mt, 2H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 102

The operation is carried out as described in Example 87 but by stirringthe reaction mixture for 4 days at 20° C., starting with 0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.023 g of2(RS),6(RS)-dimethylpiperidine. The crude product is chromatographed ona silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height8 cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 9 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.024 g of1-{(R*)-(4-chlorophenyl)[4-(2(RS),6(RS)dimethyl(piperadin-1-ylmethyl)phenyl]methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃ with addition of a few drops of CD₃COOD-d4, at atemperature of 353K, □ in ppm): from 1.20 to 1.45 (mt, 2H), 1.60 (d, J=7Hz, 6H), from 1.80 to 2.10 (mt, 4H), 2.80 (s, 3H), 3.17 (mt, 2H), 3.90(mt, 2H), 4.34 (broad d, J=16 Hz, 1H), 4.40 (mt, 2H), 4.43 (broad d,J=16 Hz, 1H), 4.62 (s, 1H), 6.82 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt,2H), from 7.20 to 7.50 (mt, 8H)].

EXAMPLE 103

The operation is carried out as described in Example 87, but by stirringthe reaction mixture for 4 days at 20° C., starting with 0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.024 g ofpiperazin-2-one. The crude product is chromato-graphed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 2.5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 8 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.022 g of1-{(R*)-(4-chlorophenyl)[4-(piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene}azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, □ in ppm): 2.62 (t, J=5.5 Hz, 2H), 2.80 (s, 3H), 3.11(s, 2H), 3.34 (mt, 2H), 3.51 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.51(s, 1H), 5.76 (unresolved complex, 1H), 6.84 (broad t, J_(HF)=9 Hz, 1H),6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 104

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.020 g of L-prolinol. Thecrude product is chromatographed on a silica gel column (particle size0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.028 g of1-{{(R*)-(4-chlorophenyl){4-[(2S)-(hydroxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): from 1.50 to 2.00 (mt, 4H), 2.24 (mt, 1H),2.71 (mt, 1H), 2.80 (s, 3H), 2.93 (mt, 1H), 3.28 (d, J=13.5 Hz, 1H),3.45 (mt, 1H), 3.65 (d, J=11 and 4 Hz, 1H), 3.84 (mt, 2H), 3.91 (d,J=13.5 Hz, 1H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz,1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 105

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.023 g of(2S)-(methoxymethyl)pyrrolidine. The crude product is chromatographed ona silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height8 cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 6 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.037 g of1-{{(R*)-(4-chlorophenyl){4-[(2S)-(methoxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 1.66 (mt, 2H), 1.90 (mt, 1H), 2.16 (mt, 1H),2.68 (mt, 1H), 2.80 (s, 3H), 2.89 (mt, 1H), from 3.25 to 3.45 (mt, 4H),3.31 (s, 3H), 3.84 (mt, 2H), 4.04 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H),4.50 (s, 1H), 6.44 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20to 7.40 (mt, 8H)].

EXAMPLE 106

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.020 g of2(RS),5(RS)-dimethylpyrrolidine. The crude product is chromatographed ona silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height8 cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture. Fractions 3 to 6 are combined andthen concentrated to dryness under reduced pressure (2.7 kPa). 0.024 gof1-{(R*)-(4-chlorophenyl)[4-(2(RS),5(RS)-dimethylpyrrolidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,mixture of isomers, form A, is obtained in the form of a white foam [¹HNMR spectrum (400 MHz, CDCl₃ with addition of a few drops of CD₃COOD-d4,□ in ppm): 1.68 (d, J=7 Hz, 6H), from 2.00 to 2.15 (mt, 4H), 2.82 (s,3H), 3.22 (mt, 2H), 3.92 (mt, 2H), 4.30 (s, 2H), 4.33 (mt, 1H), 4.45 (d,J=16.5 and 3 Hz, 1H), 4.63 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H),7.00 (mt, 2H), from 7.20 to 7.55 (mt, 8H)].

EXAMPLE 107

The operation is carried out as described in Example 87, starting with0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.023 g of L-prolinamide.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 5 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.028 g of1-{(R*)-(4-chlorophenyl)[4-((2S)-carbamoylpyrrolidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, □ in ppm): from 1.65 to 1.85 (mt, 2H), 1.92 (mt, 1H),from 2.15 to 2.35 (mt, 2H), 2.80 (s, 3H), 3.00 (mt, 1H), 3.16 (dd, J=10and 5.5 Hz, 1H), 3.41 (d, J=13.5 Hz, 1H), 3.86 (mt, 2H), 3.89 (d, J=13.5Hz, 1H), 4.33 (mt, 2H), 4.51 (s, 1H), 5.23 (unresolved complex, 1H),6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), 7.17 (unresolved complex,1H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 108

The operation is carried out as described in Example 87, but by stirringthe reaction mixture for 4 days at 20° C., starting with 0.05 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.021 g of diethanolamine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 9 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.004 g of1-{(R*)-(4-chlorophenyl)[4-(dihydroxyehtylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 2.69 (t, J=5.5 Hz, 4H), 2.80 (s, 3H), 3.61(t, J=5.5 Hz, 4H), 3.65 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s,1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40(mt, 8H)].

EXAMPLE 109

0.055 g of imidazole is added to solution of 0.24 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, in 5 cm³ of dichloromethane. After heating for 3 hoursunder reflux, the mixture is supplemented with 5 mg of sodium iodide.After stirring for 20 hours under reflux, the reaction mixture is cooledto 20° C. and then chromatographed on a silica gel column (particle size0.06-0.200 mm, diameter 1.0 mm, height 20 cm), eluting with 120 cm³ ofdichloromethane without fractionating, and then with a dichloromethaneand methanol mixture (98/2 and then 96/4 by volume), collecting 4 cm³fractions. Fractions 12 to 14 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 0.039 g of1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam.

EXAMPLE 110

The operation is carried out as described in Example 87, starting with0.50 g of1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, 5 mg of sodium iodide, 15 cm³ of dichloromethane and0.0190 g of pyrrolidine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 1.5 mm, height20 cm), at an argon pressure of 0.1 bar, eluting with dichloromethaneand then with a dichloromethane and methanol mixture (95/5 by volume)and collecting 25 cm³ fractions. Fractions 20 to 40 are combined andthen concentrated to dryness under reduced pressure (2.7 kPa). 0.028 gof1-{(R*)-(4-chlorophenyl)[4-(pyrrolidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white foam. [a]²⁰365nm=+26.8°±0.8 (c=0.5%, dichloromethane) [¹H NMR spectrum (300 MHz,CDCl₃, □ in ppm): 1.78 (mt, 4H), 2.50 (mt, 4H), 2.80 (s, 3H), 3.57 (s,2H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, may be prepared by carrying out the operation asdescribed in Example 87, starting with 7.3 g of the mixture of the 2diastereoisomers (B forms)1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine-3-oland1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)-methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)-methyl]azetidin-3-ol,8.2 g of 4-dimethylaminopyridine, 150 cm³ of dichloromethane and 3.2 cm³of methanesulfonyl chloride. The crude product is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30cm), at an argon pressure of 0.2 g bar, eluting with dichloromethane andcollecting 100 cm³ fractions. Fractions 15 to 30 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 2.50 g of1-{(R*)-[4-(chloromethyl)phenyl]-(4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, are obtained in the form of a white foam.

The mixture of the 2 diastereoisomers1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)-methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)-methyl]azetidin-3-ol,may be prepared by carrying out the operation as described in Example87, starting with 11.0 g of a mixture of the 2 diastereoisomers1-{(R*)-[4-(chlorophenyl)[4-(hydroxymethyl)phenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland1-{(R*)-[4-(chlorophenyl)]4-(hydroxymethyl)phenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,250 cm³ of dichloromethane and 3.1 cm³ of thionyl chloride. The crudeproduct is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.2bar, eluting with a cyclohexane and ethyl acetate mixture (70/30 byvolume) and collecting 50 cm³ fractions. Fractions 9 to 25 are combinedand then concentrated to dryness under reduced pressure (2.7 kPa). 7.3 gof the mixture of the 2 diastereoisomers (B forms)1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)-methyl]azetidin-3-olare obtained in the form of a white foam.

The mixture of the 2 diastereoisomers (B forms)1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-olmay be prepared by carrying out the operation as described in Example87, starting with 18.0 g of the mixture of the 2 diastereoisomers (Bforms)3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methyloxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidine,150 cm³ of anhydrous toluene and 100 cm³ of a 20% solution ofdiisobutylaluminum hydride in toluene. The crude product ischromatographed on a silica gel column (particle size 0.06-0.200 mm,diameter 3cm, height 30 cm), at an argon pressure of 1 bar, eluting witha cyclohexane and ethyl acetate mixture (50/50 by volume) and collecting50 cm³ fractions. Fractions 15 to 30 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 11.0 g of the mixture ofthe 2 diastereoisomers (B forms)1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-olare obtained in the form of a white foam.

The mixture of the 2 diastereoisomers (B forms)3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidinemay be prepared by carrying out the operation as described in Example40, starting with 11.2 g of (3,5-difluorobenzyl)methylsulfone, 350 cm³of tetrahydrofuran, 34 cm³ of a 1.6 N solution of n-butyllithium inhexane, 11.2 g of1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-azetidin-3-one,form B isomer, and 5.5 cm³ of acetyl chloride. The crude product ischromatographed on a silica gel column (particle size 0.06-0.200 mm,diameter 4 cm, height 40 cm), eluting with a cyclohexane and ethylacetate mixture (70/30 by volume) and collecting 100 cm³ fractions.Fractions 10 to 30 are combined and then concentrated to dryness underreduced pressure (2.7 kPa). 21 g of a still impure cream-colored foamare obtained, which foam is chromatographed on a silica gel column(particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting withdichloromethane and collecting 100 cm³ fractions. Fractions 11 to 30 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 20.0 g of the mixture of the 2 diastereoisomers (B forms)3-acetoxy-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand3-acetoxy-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineare obtained in the form of a white foam.

1{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one,form B isomer, may be prepared by carrying out the operation asdescribed in Example 40, starting with 8.7 cm³ of oxalyl chloride, 350cm³ of dichloromethane, 14.2 cm³ of dimethyl sulfoxide, 29.0 g of1{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ole,form B isomer, and 43 cm³ of triethylamine. The crude product ischromatographed on a silica gel column (particle size 0.06-0.200 mm,diameter 4 cm, height 40 cm), eluting with dichloromethane andcollecting 250 cm³ fractions. Fractions 7 to 25 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of1{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol,form B isomer, may be prepared according to the procedure described byKATRITZKY A. R., et al., in J. Heterocycl. Chem., (1994), 271, startingwith 25.5 g ofmethyl(−)-4-[1-(R*)-amino-1-(4-chlorophenyl)methyl]benzoate, 250 cm³ ofethanol, 7.9 g of sodium hydrogen carbonate, and 7.7 cm³ ofepibromohydrin. 29 g of1{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol,form B isomer, are obtained in the form of a yellow oil.

Methyl(−)-4[(R*)amino(4-chlorophenyl)methyl]benzoate, may be prepared bycarrying out two successive recrystallizations of the white crystals(3.4 g) called “A crystals” of Example 87, from 68 cm³ of ethanolcontaining 5% water under reflux. The crystals obtained are filtered,drained and then dried under reduced pressure (2.7 kPa). 2.2 g ofmethyl(−)-4-[(R*)amino(4-chlorophenyl)methyl]benzoate D-(−)-tartrate areobtained in the form of white crystals which are dissolved in 50 cm³ ofethyl acetate. The solution obtained is supplemented with 50 cm³ of 1 Nsodium hydroxide, stirred and then separated after settling out. Theorganic phase is washed with 50 cm³ of water and then dried overmagnesium sulfate and concentrated to dryness under reduced pressure(2.7 kPa). 1.9 g ofmethyl(−)-4-[(R*)amino(4-chlorophenyl)methyl]benzoate are obtained inthe form of a white solid [a]20° C., 365 nm=˜58.1°±1 (c=0.5%)

EXAMPLE 111

The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ ofN-methylpiperazine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm),eluting with 50 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 3 cm³ fractionsimmediately after using this eluent mixture. Fractions 4 to 10 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.025 g of1-{(R*)-[4-(chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, is obtained in the form of a cream-colored foam [¹H NMRspectrum (300 MHz, CDCl₃, □ in ppm): 2.28 (s, 3H), 2.44 (unresolvedcomplex, 8H), 2.80 (s, 3H), 3.5 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H),4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to7.40 (mt, 8H)].

EXAMPLE 112

The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ of L-Prolinol.The crude product is chromatographed on a silica gel column (particlesize 0.06- 0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 3 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.025 g of1-{{(R*)-(4-chlorophenyl){4-[(2S)(hydroxymethyl)-pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a cream-colored foam [¹H NMRspectrum (300 MHz, CDCl₃, □ in ppm): from 1.80 to 2.00 (mt, 4H), 2.24(mt, 1H), 2.72 (mt, 1H), 2.80 (s, 3H), 2.94 (mt, 1H), 3.28 (d, J=13.5Hz, 1H), 3.45 (mt, 1H), 3.65 (d, J=10.5 and 3.5 Hz, 1H), 3.85 (mt, 2H),3.92 (d, J=13.5 Hz, 1H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)].

EXAMPLE 113

The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ of D-Prolinol.The crude product is chromatographed on a silica gel column (particlesize 0.06- 0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 3 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 9 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.029 g of1-{{(R*)-(4-chlorophenyl){4-(2R)(hydroxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a cream-colored foam [¹H NMRspectrum (300 MHz, CDCl₃, □ in ppm): from 1.50 to 2.00 (mt, 4H), 2.24(mt, 1H), 2.71 (mt, 1H), 2.81 (s, 3H), 2.93 (mt, 1H), 3.28 (d, J=13.5Hz, 1H), 3.44 (split t, J=10.5 and 2.5 Hz, 1H), 3.66 (dd, J=10.5 and 3.5Hz, 1H), 3.85 (mt, 2H), 3.92 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H), 4.50 (s,1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40(mt, 8H)].

EXAMPLE 114

The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ of morpholine.The crude product is chromatographed on a silica gel column (particlesize 0.06- 0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 3 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.047 g of1-{(R*)-(4-chlorophenyl)[4-(morpholin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): 2.40 (mt, 4H), 2.81 (s, 3H), 3.43 (s, 2H),3.69 (mt, 4H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt,J=8.5 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 115

The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ ofthiomorpholine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06- 0.200 mm, diameter 8 mm, height 5 cm),eluting with 50 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 3 cm³ fractionsimmediately after using this eluent mixture. Fractions 2 to 9 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.047 g of1-{(R*)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, □ in ppm): from 2.60 to 2.75 (mt, 8H), 2.81 (s, 3H),3.44 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt,J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)].

EXAMPLE 116

The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with0.200 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, 5.0 cm³ of dichloromethane and 0.120 cm³ ofpiperazin-2-one. The crude product is chromatographed on a silica gelcolumn (particle size 0.06- 0.200 mm, diameter 1.0 cm, height 10 cm),eluting with 50 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 13 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.090 g of1-{(R*)-(4-(chlorophenyl)[4-(piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white powder.

EXAMPLE 117

The operation is carried out as described in Example 110 starting with0.200 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 5.0 cm³ of dichloromethane and 0.120 of3,3-dimethylpiperidine. The crude product is chromatographed on a silicagel column (particle size 0.06- 0.200 mm, diameter 1.0 cm, height 10cm), eluting with 50 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 5 cm³fractions immediately after using this eluent mixture. Fractions 4 to 11are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.120 g of1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpiperidinylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white powder.

EXAMPLE 118

The operation is carried out as described in Example 110, by stirringfor 72 hours at 20° C., starting with 0.200 g of1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 5.0 cm³ of dichloromethane and 0.080 of imidazole. Thereaction mixture is directly chromatographed on a silica gel column(particle size 0.06- 0.200 mm, diameter 1.0 cm, height 10 cm), elutingwith 100 cm³ of dichloromethane without fractionating, and then with adichloromethane and methanol mixture (98/2 and then 96/4 by volume),collecting 5 cm³ fractions. Fractions 5 to 12 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.34 g of1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]}azetidine,form B isomer, is obtained in the form of a white powder. [a]²⁰D=−6.7°(c=0.5% dichloromethane)

EXAMPLE 119

2.47 g of potassium tert-butoxide are added to a suspension of 6.12 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.15 g of methyl5-(methylsulfonylmethyl)thiophene-2-carboxylate in 200 cm³ oftetrahydrofuran, under an argon atmosphere, cooled to −70° C. Themixture is stirred for 1 hour 30 min at a temperature close to −70° C.,and then 1.7 cm³ of methanesulfonyl chloride in solution in 8 cm³ ofethyl ether is added. After stirring for 1 hour at a temperature closeto −70° C., the mixture is allowed to return to room temperature andthen 80 cm³ of distilled water are added. The mixture is concentrated ina rotary evaporator to one third of its initial volume, and is thenextracted with 500 cm³ of dichloromethane. The organic phase is washedwith three times 80 cm³ of distilled water, dried over magnesium sulfateand concentrated to dryness under reduced pressure (2.7 kPa). Theresidue obtained is chromatographed on a silica gel column (particlesize 0.02-0.04 mm, diameter 7.5 cm, height 35 cm), eluting at a nitrogenpressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30by volume) and collecting 40 cm³ fractions. Fractions 19 to 29 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 1.6 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidineare obtained in the form of a cream-colored foam [¹H NMR spectrum (400MHz, CDCl₃, □ in ppm): 2.91 (s, 3H), 4.08 (mt, 2H), 4.37 (mt, 2H), 4.53(s, 1H), from 7.25 to 7.45 (mt, 9H), 7.71 (d, J=3.5 Hz, 1H)].

Fractions 34 to 48 are combined and then concentrated to dryness underreduced pressure (2.7 kPa). 2.6 g of(RS)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidineare obtained in the form of a cream-colored powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 2.87 (s, 3H), 2.89 (d, J=8 Hz, 1H), 2.96(d, J=8 Hz, 1H), 3.21 (d, J=8 Hz, 1H), 3.76 (d, J=8 Hz, 1H), 3.82 (s,3H), 4.55 (s, 1H), 4.86 (s, 1H), 6.86 (s, 1H), from 7.35 to 7.45 (mt,9H), 7.73 (d, J=4 Hz, 1H)].

Methyl 5-(methylsulfonylmethyl)thiophene-2-carboxylate may be preparedin the following manner: 6.94 g of sodium methanesulfinate are added, atroom temperature, to a solution of 16 g of methyl5-bromomethylthiophene-2-carboxylate in 150 cm³ of tetrahydrofuran. Thesuspension is stirred for 2 hours 30 min under reflux, and then afteraddition of 50 cm³ of ethanol is again stirred for 3 hours under reflux.The mixture is concentrated to dryness under reduced pressure (2.7 kPa)and the residue obtained is supplemented with 150 cm³ of distilled waterand is then extracted with twice 300 cm³ of ethyl acetate. The organicphase is successively washed with 100 cm³ of distilled water and twice50 cm³ of saturated aqueous sodium chloride solution and then dried overmagnesium sulfate and concentrated to dryness under reduced pressure(2.7 kPa). 14 g of methyl5-(methylsulfonylmethyl)thiophene-2-carboxylate are thus obtained in theform of a yellow solid melting around 133° C. [¹H NMR spectrum (400 MHz,(CD₃)₂SO-d6, at a temperature of 373 K, □ in ppm): 3.05 (s, 3H), 4.22(mt, 2H), 4.40 (mt, 2H), 4.98 (broad s, 1H), 7.30 (d, J=3.5 Hz, 1H),7.39 (d, J=8 Hz, 4H), 7.50 (d, J=8 Hz, 4H), 7.66 (d, J=3.5 Hz, 1H)].

Methyl 5-bromomethylthiophene-2-carboxylate may be prepared according toCurtin M. L., Davidsen S. K., Heyman H. R., Garland R. B., Sheppard G.S., J. Med. Chem., 1998, 41 (1), 74-95.

EXAMPLE 120

47 μl of N,N′-diisopropylcarbodiimide, 3.36 mg of4-dimethylaminopyridine and 60 μl of isobutylamine are added to asolution of 163.5 mg of1-[bis(4-chlorophenyl)methyl]-3-](methylsulfonyl)(2-hydroxycarbonylthien-5-yl)methylene]azetidinehydrochloride in 3 cm³ of dichloromethane, at room temperature. Themixture is stirred for 18 hours at room temperature and thenchromatographed on a silica gel column (particle size 0.04-0.06 mm),eluting with a dichloromethane and ethyl acetate mixture (90/10 byvolume). 60 mg of1-[bis(4-chlorophenyl)methyl]-3-[2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidineare thus obtained in the form of a colorless lacquer [¹H NMR spectrum(400 Hz, CDCl₃, □ in ppm): 0.97 (d, J=7 Hz, 6H), 1.88 (mt, 1H), 2.90 (s,3H), 3.25 (t, J=7 Hz, 2H), 4.08 (mt, 2H), 4.36 (mt, 2H), 4.52 (s, 1H),4.56 (broad t, J=7 Hz, 1H), from 7.20 to 7.40 (mt, 10H)].

1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-hydroxycarbonylthien-5-yl)methylene]azetidinehydrochloride may be prepared in the following manner: 250 cm³ ofconcentrated hydrochloric acid are added to a solution of 14 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidinein 250 cm³ of acetic acid, at room temperature. The mixture is stirredfor 38 hours at a temperature of 50° C. and is then concentrated todryness under reduced pressure (2.7 kPa). Three times, the residue issupplemented with 250 cm³ of toluene and concentrated to dryness underreduced pressure (2.7 kPa). After trituration of the residue in 400 cm³of ethyl ether, 14.2 of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-hydroxycarbonylthien-5-yl)methylene]azetidinehydrochloride are obtained in the form of a beige powder.

EXAMPLE 121

0.37 g of potassium tert-butoxide is added to a solution of 0.92 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 0.75 g of[(3-methoxycarbonylphenyl)methyl]methylsulfone in 30 cm³ oftetrahydrofuran, under an argon atmosphere, cooled to −70° C., and themixture is stirred for 2 hours at −70° C. 10 cm³ of a 0.1 N solution ofhydrochloric acid are then added and the mixture is allowed to return toroom temperature. After addition of 50 cm³ of ethyl acetate, thereaction mixture is separated after settling out, dried over magnesiumsulfate, filtered and then concentrated to dryness under reducedpressure (2.7 pKa). The residue is chromatographed on a silica gelcolumn (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm),eluting at a nitrogen pressure of 0.8 bar with a cyclohexane and ethylacetate mixture (70/30 by volume) and collecting 120 cm³ fractions.Fractions 11 to 18 are combined and then concentrated to dryness underreduced pressure (2.7 kPA). The residue is crystallized from 10 cm³ ofisopropyl ether and 30 cm³ of pentane. 0.30 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl(RS)azetidin-3-ol is thus obtained in the form of a white solid [¹H NMRspectrum (400 MHz, CDCl₃, □ in ppm): 2.73 (s, 3H), 3.05 (AB, J=9 Hz,2H), 3.27 (d, J=9 Hz, 1H), 3.63 (s, 1H), 3.79 (d, J=9 Hz, 1H), 3.95 (s,3H), 4.32 (s, 1H), 4.59 (s, 1H), from 7.15 to 7.35 (mt, 8H), 7.51 (t,J=8 Hz, 1H), 7.94 (broad d, J=8 Hz, 1H), 8.10 (broad d, J=8 Hz, 1H),8.32 (broad s, 1H))].

EXAMPLE 122

By carrying out the operation according to the procedure of Example 1,starting with 0.66 g of methyl(pyridin-4-ylmethyl)sulfone and 1.18 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 0.20 g of a whit solid isobtained after purification on a silica gel column (particle size0.20-0.06 mm, diameter 3 cm, height 50 cm), at a nitrogen pressure 0.5bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) aseluent and collecting 120 cm³ fractions. The solid is taken up in 20 cm³of diisopropyl ether. After filtration, draining and drying, 0.16 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS)]-azetidin-3-olis obtained [¹H NMR spectrum (400 MHz, CDCl₃, □ in ppm): 2.76 (s, 3H),3.03 (AB, J=9 Hz, 2H), 3.27 (d, J=9 Hz, 1H), 3.53 (s, 1H), 3.83 (d, J=9Hz, 1H), 4.32 (s, 1H), 4.51 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.63(d, J=6 Hz, 2H), 8.68 (d, J=6 Hz, 2H)].

Methyl(pyridin-4-ylmethyl)sulfone may be prepared according to thereference JP43002711.

EXAMPLE 123

By carrying out the operation according to the procedure of Example 1,starting with 0.47 g of methyl(pyridin-3-ylmethyl)sulfone and 0.83 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 0.50 g of a whit solid isobtained after purification on a silica gel column (particle size0.20-0.06 mm, diameter 3 cm, height 50 cm), at a nitrogen pressure 0.5bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) aseluent and collecting 120 cm³ fractions. The solid is taken up in 30 cm³of diisopropyl ether. After filtration, draining and drying, 0.40 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)methyl-(RS)]-azetidin-3-olis obtained [¹H NMR spectrum (300 MHz, CDCl₃, □ in ppm): 2.77 (s, 3H),3.03 (AB, J=9 Hz, 2H), 3.28 (d, J=9 Hz, 1H), 3.66 (s, 1H), 3.83 (d, J=9Hz, 1H), 4.33 (s, 1H), 4.55 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.37(dd, J=8 and 5 Hz, 1H), 8.16 (dt, J=8 and 2 Hz, 1H), 8.68 (dd, J=5 and1.5 Hz, 1H), 8.83 (d, J=2 Hz, 1H)].

Methyl(pyridin-3-ylmethyl)sulfone may be prepared according to thereference JP43002711.

EXAMPLE 124

0.0388 cm³ of N-(3-aminopropyl)morpholine is added, at the sametemperature, to a suspension of 150 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid activated on TFP resin (165 μM) in 3 cm³ of dichloromethane,pre-stirred for 90 minutes at a temperature close to 20° C. Thesuspension is stirred at a temperature close to 20° C. for 22 hours andthen filtered on sintered glass. The solid residue is rewashed withtwice 1.5 cm³ of dichloromethane. The filtrates are combined andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature close to 40° C. 60 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamideare thus obtained in the form of a pale yellow foam.

3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamidemay also be prepared in the following manner: 0.083 cm³ ofN-(3-aminopropyl)morpholine, 110 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 5 mg of4-dimethylaminopyridine are successively added to a solution of 300 mgof3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid in 10 cm³ of anhydrous dichloromethane (over calcium chloride) and5 cm³ of dimethylformamide, under an inert atmosphere of nitrogen, at atemperature close to 20° C. The solution obtained is stirred at atemperature close to 20° C. for about 22 hours and then concentrated todryness under reduced pressure (0.27 kPa) at a temperature close to 40°C. The solid residue is taken up in 25 cm³ of dichloromethane and washedwith twice 20 cm³ of a saturated aqueous sodium bicarbonate solution.After separation after settling out, the organic phase is dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) at a temperature close to 40° C. 400 mg of a yellowoil are thus obtained, which oil is purified by chromatography under anitrogen pressure (0.8 bar) on 60 cm³ of silica (0.040-0.063 mm)contained in a column 2.2 cm in diameter, eluting with amethanol/dichloromethane mixture (2-98 by volume). The fractionscontaining only the desired product are combined and concentrated todryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours. 130 mgof3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamideare thus obtained in the form of a white crystalline powder [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d6, □ in ppm): 1.68 (mt, 2H), from 2.25 to2.40 (mt, 6H), 2.97 (s, 3H), from 3.20 to 3.35 (mt, 2H), 3.57 (t, J=4.5Hz, 4H), 3.81 (mt, 2H), 4.22 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz,4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s,1H), 7.86 (broad d, J=8 Hz, 1H), 8.53 (t, J=5.5 Hz, 1H)].

EXAMPLE 125

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.033 cm³ of N,N-dimethyl-1,3-propanediamine. 52 mg of3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 1.65 (mt, 2H), 2.18 (s, 6H), from 2.20 to2.35 (mt, 2H), 2.98 (s, 3H), from 3.25 to 3.45 (mt, 2H), 3.82 (mt, 2H),4.23 (mt, 2H), 4.80 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.56 (d, J=8.5 Hz,4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.57 (t, J=5.5 Hz, 1H)].

EXAMPLE 126

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0333 cm³ of 1-(aminoethyl)pyrrolidine.39 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamideare thus obtained in the form of a pale yellow powder [¹H NMR spectrum(300 MHz, (CD₃)₂SO-d6 with addition of a few drops of CD₃COOD-d4, □ inppm): from 1.80 to 2.00 (mt, 4H), 2.97 (s, 3H), 3.20 (mt, 6H), 3.57 (t,J=6.5 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.77 (s, 1H), 7.35 (d,J=8.5 Hz, 4H), 7.45 (d, J=8.5 Hz, 4H), from 7.50 to 7.65 (mt, 2H), 7.87(broad s, 1H), 7.90 (broad d, J=7.5 Hz, 1H)].

EXAMPLE 127

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0333 cm³ of1-(dimethylamino)-2-propylamine. 49 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 1.13 (d, J=6.5 Hz, 3H), from 2.10 to 2.25(mt, 1H), 2.15 (s, 6H), 2.38 (dd, J=13 and 8 Hz, 1H), 2.98 (s, 3H), 3.80(mt, 2H), 4.14 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz,4H), from 7.45 to 7.60 (mt, 2H), 7.46 (d, J=8 Hz, 4H), 7.83 (broad s,1H), 7.87 (broad d, J=8 Hz, 1H), 8.16 (broad d, J=8 Hz, 1H)].

EXAMPLE 128

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.026 cm³ of piperidine. 56 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-piperidin-1-ylbenzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): from 1.45 to 1.70 (mt, 6H), from 2.90 to3.05 (mt, 2H), 2.98 (s, 3H), 3.19 (unresolved complex, 1H), 3.57(unresolved complex, 1H), 3.85 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H),from 7.30 to 7.55 (mt, 12H)].

EXAMPLE 129

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0265 cm³ of isobutylamine. 46 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-isobutylbenzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 0.89 (d, J=7 Hz, 6H), 1.85 (mt, 1H), 2.98(s, 3H), 3.09 (t, J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s,1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60(mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.51 (t, J=6Hz, 1H)].

EXAMPLE 130

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0316 cm³ of N-(3-aminopropyl)imidazole.54 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamideare thus obtained in the form of a yellow foam [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 1.97 (mt, 2H), 2.98 (s, 3H), 3.25 (mt, 2H),3.81 (mt, 2H), 3.81 (mt, 2H), 4.02 (t, J=7 Hz, 2H), 4.23 (mt, 2H), 4.79(s, 1H), from 6.85 to 6.95 (mt, 2H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d,J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88(broad d, J=8 Hz, 1H), 8.50 (t, J=5.5 Hz, 1H)].

EXAMPLE 131

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.030 cm³ ofN,N-(dimethyl)ethylenediamine. 53 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-dimethylaminoethyl)benzamideare thus obtained in the form of an ochre-colored foam [¹H NMR spectrum(400 MHz, (CD₃)₂SO-d6, □ in ppm): 2.18 (2s, 6H), from 2.35 to 2.45 (mt,2H), 2.98 (s, 3H), from 3.25 to 3.50 (mt, 2H), 3.81 (mt, 2H), 4.23 (mt,2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.43(t, J=6.5 Hz, 1H) .

EXAMPLE 132

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0141 cm³ of methylhydrazine. 42 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid N′methylhydrazide are thus obtained in the form of a pale yellowfoam [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, □ in ppm): 2.96 (s, 3H),3.18 (broad s, 3H), 3.83 (mt, 2H), 4.22 (mt, 2H), 4.80 (broad s, 2H),from 7.35 to 7.65 (mt, 12H)].

EXAMPLE 133

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0345 cm³ of N-(2-aminoethyl)morpholine.62 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamideare thus obtained in the form of an ochre-colored foam. [¹H NMR spectrum(400 MHz, (CD₃)₂SO-d6, □ in ppm): from 2.30 to 2.45 (mt, 4H), 2.46 (t,J=7.5 Hz, 2H), 2.98 (s, 3H), 3.38 (mt, 2H), from 3.50 to 3.65 (mt, 4H),3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46(d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.85(dd, J=8 and 2 Hz, 1H), 8.45 (t, J=6.5 Hz, 1H)].

EXAMPLE 134

The operation is carried out under the conditions described in Example124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 82 M) and 0.0396 cm³ of2-(aminomethyl)-N-ethylpyrrolidine. 58 g of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamideare thus obtained in the form of an ochre-colored foam.

3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamidemay also be prepared under the conditions described in Example 126starting with 700 mg activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (770 μM). 0.0324 cm³ of triethylamine and 0.25 cm³ of2-(aminomethyl)-N-ethylpyrrolidine. 370 mg of a solid are thus obtained,which solid is purified by chromatography under nitrogen pressure (0.7bar) on 100 cm³ of silica (0.040-0.063 mm) contained in a column 2.5 cmin diameter, eluting with a methanol-dichloromethane mixture (15-85 byvolume). The fractions containing only the desired product are combinedand concentrated to dryness under reduced pressure (0.27 kPa) at 40° C.for 2 hours. 160 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamideare thus obtained in the form of a pale yellow powder [¹ H NMR spectrum(400 MHz, (CD₃)₂SO-d6, □ in ppm): 1.04 (t, J=7 Hz, 3H), from 1.50 to1.70 (mt, 3H), 1.78 (mt, 1H), 2.14 (mt, 1H), 2.28 (mt, 1H), 2.59 (mt,1H), 2.83 (mt, 1H), 2.98 (s, 3H), from 3.00 to 3.15 (mt, 2H), from 3.30to 3.45 (mt, 1H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d,J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86(broad s, 1H), 7.85 (broad d, J=8 Hz, 1H), 8.41 (t, J=6 Hz, 1H)].

EXAMPLE 135

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.023 cm³ of neopentylamine. 69 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamideare thus obtained in the form of a pale yellow powder [¹H NMR spectrum(400 MHz, (CD₃)₂SO-d6, □ in ppm): 0.90 (s, 9H), 2.98 (s, 3H), 3.11 (d,J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broads, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.37 (t, J=6.5 Hz, 1H)].

EXAMPLE 136

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.025 cm³ of aminomethylcyclohexane. 44mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclohexylmethylbenzamideare thus obtained in the form of a pale yellow powder whosecharacteristics are the following [¹H NMR spectrum (400 MHz,(CD₃)₂SO-d6, □ in ppm): 0.92 (mt, 2H), 1.17 (mt, 4H), from 1.45 to 1.80(mt, 5H), 2.97 (s, 3H), 3.10 (d, J=6 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt,2H), 4.79 s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.47(t, J=6 Hz, 1H)].

EXAMPLE 137

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM), 0.026 cm³ of triethylamine and 21 mg ofaminomethylcyclopropane hydrochloride. 68 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclopropylmethylbenzamideare thus obtained in the form of a yellow foam [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt,1H), 2.98 (s, 3H), 3.15 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H),4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.89 (broad d, J=8 Hz, 1H), 8.64(t, J=6 Hz, 1H)].

EXAMPLE 138

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.023 cm³ of 2-methylbutylamine. 49 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-methylbutyl)benzamideare thus obtained [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, □ in ppm):from 0.80 to 0.95 (mt, 6H), from 1.05 to 120 (mt, 1H), 1.41 (mt, 1H),1.64 (mt, 1H), 2.98 (s, 3H), 3.06 (mt, 1H), 3.19 (mt, 1H), 3.81 (mt,2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4 H), 7.46 (d, J=8Hz, 4H), from 7.35 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.87 (broad d,J=8 Hz, 1H), 8.49 (t, J=5.5 Hz, 1H)].

EXAMPLE 139

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.028 cm³ of 2-methylphenethylamine. 42mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-phenylpropyl)benzamideare thus obtained in the form of a yellow paste [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 1.24 (d, J=7 Hz, 3H), 2.97 (s, 3H), 3.07(mt, 1H), from 3.20 to 3.50 (mt, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.80(s, 1H), from 7.10 to 7.40 (mt, 5H), 7.38 (d, J=8 Hz, 4H), 7.47 (d, J=8Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.77 (broad s, 1H), 7.79 (broad d,J=8 Hz, 1H), 8.55 (t, J=6 Hz, 1H)].

EXAMPLE 140

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.020 cm³ oftetrahydrofurfurylmethylamine. 42 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamideare thus obtained in the form of a yellow paste [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 1.58 (mt, 1H), from 1.75 to 2.00 (mt, 3H),2.98 (s, 3H), from 3.20 to 3.40 (mt, 2H), 3.63 (mt, 1H), 3.77 (mt, 1H),3.82 (mt, 2H), 3.98 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broads, 1H),

EXAMPLE 141

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 39 mg of 2,2-diphenylethylamine. 39 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamideare thus obtained in the form of a yellow paste [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 2.95 (s, 3H), 3.77 (mt, 2H), 3.90 (dd, J=8and 6.5 Hz, 2H), 4.22 (mt, 2H), 4.42 (t, J=8 Hz, 1H), 4.79 (s, 1H), from7.10 to 7.40 (mt, 10H), 8.56 (t, J=6.5 Hz, 1H)].

EXAMPLE 142

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 19 mg of 2-ethylbutylamine. 47 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-ethylbutyl)benzamideare thus obtained in the form of a yellow powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 0.86 (t, J=7 Hz, 6H), from 1.20 to 1.40(mt, 4H), 1.50 (mt, 1H), 2.98 (s, 3H), 3.19 (t, J=6 Hz, 2H), 3.82 (mt,2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d,J=8 Hz, 1H), 8.42 (t, J=6 Hz, 1H)].

EXAMPLE 143

The operation is carried out under the conditions described in Example124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM), 0.026 cm³ of triethylamine and 39 mg of4-aminoethylcyclohexanecarboxylic acid methyl ester hydrochloride. 47 mgof4-{(3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylicacid methyl ester are thus obtained in the form of a yellow paste [¹HNMR spectrum (400 MHz, (CD₃)₂SO-d6, □ in ppm): from 0.90 to 1.05 (mt,2H), from 1.20 to 1.40 (mt, 2H), 1.52 (mt, 1H), from 1.70 to 2.00 (mt,4H), 2.27 (mt, 1H), 2.98 (s, 3H), 3.12 (t, J=6.5 Hz, 2H), 3.60 (s, 3H),3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46(d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.87(broad d, J=8 Hz, 1H), 8.50 (t, J=6 Hz, 1H)].

Activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin may be prepared under the following conditions: 1.18 gof3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid is added, at the same temperature, to a suspension of 1.07 g of TFPresin (free phenol function, 1.1 mmol/g, that is to say 1.17 mM) in 15cm³ of anhydrous dimethylformamide, prestirred for 10 minutes at atemperature close to 20° C. After stirring for 10 minutes at atemperature close to 20° C., 14 mg of 4-dimethylaminopyridine are addedand then after stirring for 10 minutes at the same temperature, 0.185cm³ of 1,3-diisopropylcarbodiimide. After stirring for 23 hours at atemperature close to 20° C., the suspension is filtered and the resin iswashed with 45 cm³ of dimethylformamide, 45 cm³ of tetrahydrofuran, 45cm³ of dichloromethane, and then dried under vacuum to constant weight.1.5 g of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin are thus obtained in the form of a pale yellow resin.

The resin (structure below) may be prepared in the following manner:

492 mg of diisopropylcarbodiimide, 819.3 mg of2,3,5,6-tetrafluoro-4-hydroxybenzoic acid and 50 mg of4-dimethylaminopyridine are successively added to a suspension of 2 g ofcommercially available aminomethyl polystyrene resin (0.39 mmol/g; 0.78mmol) in 15 cm³ of dimethylformamide, prestirred for 5 minutes at atemperature close to 20° C. After stirring for about 20 hours at atemperature close to 20° C., the suspension is filtered and the resin isrinsed with three times 20 cm³ of dimethylformamide, three times 20 cm³of tetrahydrofuran and three times 20 cm³ of dichloromethane. The resinobtained is dried under reduced pressure at a temperature close to 40°C. The resin obtained is then stirred, at a temperature close to 20° C.,for about 20 hours, in suspension in a piperidine/dimethylformamidemixture (10/90 by volume. The suspension is filtered and the resin isrinsed with three times 20 cm³ of dimethylformamide, three times 20 cm³of tetrahydrofuran and three times 20 cm³ of dichloromethane. The resinobtained is dried under reduced pressure at a temperature close to 40°C. and is used as it is.

EXAMPLE 144

A solution of 76 mg of(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamicacid tert-butyl ester in 2.5 cm³ of formic acid is stirred for 1 hour ata temperature close to 45° C. The reaction medium is concentrated todryness under reduced pressure (5 kPa) at a temperature close to 30° C.,taken up in 10 cm³ of ethyl acetate and alkalinized with 10 cm³ of asaturated aqueous sodium bicarbonate solution. After separating aftersettling out, the organic phase is washed with 10 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 51 mg of2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-ethanoneare thus obtained in the form of a beige lacquer [¹H NMR spectrum (300MHz, CDCl₃, □ in ppm): from 1.95 to 2.25 (broad unresolved complex, 2H),2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), from 3.50 to 3.60 (mt, 2H),3.56 (broad s, 2H), from 3.75 to 3.90 (mt, 4H), 4.34 (mt, 2H), 4.50 (s,1H), 6.84 (broad d, J=8 Hz, 1H), 6.91 (dd, J=8 and 2 Hz, 1H), 7.01 (mt,1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 145

1.02 g of supported EDCI (5 mM), 44 mg of N-Boc-glycine and then 10 cm³of dichloromethane are successively added, at a temperature close to 20°C., to 108.5 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 20 hours at a temperature close to 20° C., thereaction mixture is filtered on sintered glass. The resin is rinsed withthree times 5 cm³ of dichloromethane. The combined filtrates are washedwith 20 cm³ of water, dried over magnesium sulfate, filtered on sinteredglass and concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 40° C. 143 mg of2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamicacid tert-butyl ester are thus obtained in the form of a cream-coloredlacquer [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, □ in ppm): 1.40 (s, 9H),2.93 (s, 3H), from 3.05 to 3.20 (mt, 4H), 3.57 (mt, 4H), 3.80 (mt, 2H),3.84 (d, J=6 Hz, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.79 (t, J=6 Hz, 1H),6.82 (d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5 Hz, 1H),7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].

The supported EDCI reagent is commercially available and may also beprepared according to the following reference: M. Desai, L. Stramiello,Tetrahedron Letters, 34, 48, 7685-7688 (1993).

EXAMPLE 146

A solution of 81 mg of(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene]methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester in 2.5 cm³ of formic acid is stirred for 1 hour ata temperature close to 45° C. The reaction mixture is concentrated todryness under reduced pressure (5 kPa) at a temperature close to 30° C.taken up in 10 cm³ of ethyl acetate and alkalimized with 10 cm³ of asaturated aqueous sodium bicarbonate solution. After separating aftersettling out, the organic phase is washed with 10 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 5.8 mg of1-({4-[3-(1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl]-2-methylaminoethanoneare thus obtained in the form of a beige lacquer [¹H NMR spectrum (300MHz, CDCl₃), □ in ppm): from 1.95 to 2.15 (broad unresolved complex,1H), 2.51 (broad s, 3H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), 3.49(broad s, 2H), 3.58 (mt, 2H), from 3.75 to 3.90 (mt, 4H), 4.33 (mt, 2H),4.49 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2 Hz, 1H),7.00 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 147

1.02 g of supported EDCI (5 mM), 47.3 mg of N-Boc-sarcosine and then 10cm³ of dichloromethane are successively added, at a temperature close to20° C., to 108.5 mg, of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 20 hours at a temperature close to 20° C., thereaction mixture is filtered on sintered glass. The resin is rinsed withthree times 5 cm³ of dichloromethane. The combined filtrates are washedwith 20 cm³ of water, dried over magnesium sulfate, filtered on sinteredglass and concentrated to dryness under reduced pressure (1kPa) at atemperature close to 40° C. 143 mg of(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester are thus obtained in the form of a cream-coloredlacquer [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, □ in ppm). A mixture ofrotamers is observed at room temperature; 1.31 and 1.41 (2s, 9H intotal), 2.78 and 2.8 (2s, 3H in total), 2.93 (2s, 3H), from 3.10 to 3.25(unresolved complex, 4H), from 3.45 to 3.65 (mt, 4H), 3.80 (mt, 2H),4.06 and 4.09 (2s, 2H in total), 4.19 (mt, 2H), 4.78 (s, 1H), 6.83(broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 7.00 (dd, J=8 and 2.5 Hz,1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].

EXAMPLE 148

2 cm³ of dichloromethane and then 11 mg of methyl isothiocyanate aresuccessively added, at a temperature close to 20° C., to 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 6 hours at a temperature close to 20° C., 0.05 cm³ ofwater is added to the reaction mixture. After stirring for 15 minutes atthe same temperature, the reaction medium is dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure (1kPa) at a temperature close to 40° C. 61 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioicacid N-methylamide are thus obtained in the form of a beige lacquer [¹HNMR spectrum (400 MHz, CDCl₃), □ in ppm): 2.77 (s, 3H), 3.20 (d, J=5 Hz,3H), 3.32 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.00 (t, J=5.5 Hz, 4H), 4.33(mt, 2H), 4.49 (s, 1H), 5.63 (broad q, J=5 Hz, 1H), 6.80 (d, J=8 Hz,1H), 6.85 (dd, J=8 and 2.5 Hz, 1H), 6.94 (broad s, 1H), from 7.20 to7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].

EXAMPLE 149

2 cm³ of dichloromethane and then 11.5 mg of methylisocyanate aresuccessively added, at a temperature close to 20° C., to 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 4 hours at a temperature close to 20° C., 0.05 cm³ ofwater is added to the mixture. After stirring for 15 minutes at the sametemperature, the reaction medium is dried over magnesium sulfate,filtered on paper and concentrated to dryness under reduced pressure (1kPa) at a temperature close to 40° C. 66 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid N-methylamide are thus obtained in the form of a beige lacquer [¹HNMR spectrum (400 MHz, CDCl₃), □ in ppm): 2.75 (s, 3H), 2.85 (d, J=5 Hz,3H), 3.19 (broad t, J=5.5 Hz, 4H), 3.52 (broad t, J=5.5 Hz, 4H), 3.80(mt, 2H), 4.33 (mt, 2H), 4.45 (broad q, J=5 Hz, 1H), 4.49 (s, 1H), 6.81(d, J=8 Hz, 1H), 6.89 (dd, J=8 and 2.5 Hz, 1H), 6.98 (broad s, 1H), from7.20 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].

EXAMPLE 150

2 cm³ of pyridine and then 10.4 mg of methyl chloroformate aresuccessively added, at a temperature close to 20° C., to 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 6 hours at a temperature close to 20° C., thereaction medium is concentrated to dryness under reduced pressure (5kPa) at a temperature close to 30° C. The residue obtained is taken upin 5 cm³ of ethyl acetate and 5 cm³ of water. After separating aftersettling out, the organic phase is washed with 2 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 62 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid methyl ester are thus obtained in the form of a beige lacquer [¹HNMR spectrum (400 MHz, CDCl₃), □ in ppm): 2.75 (s, 3H), 3.15 (broad t,J=5.5 Hz, 4H), 3.62 (mt, 4H), 3.74 (s, 3H), 3.80 (mt, 2H), 4.32 (mt,2H), 4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H),6.99 (broad s, 1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 151

32 mg of sodium acetoxyborohydride and then 22 mg of isobutyraldehydeare successively added, at a temperature close to 20° C., to a solution54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazinein 2 cm³ of 1,2-dichloromethane. After stirring for 4 hours at atemperature close to 20° C., 3 cm³ of dichloromethane and 2 cm³ of asaturated aqueous sodium bicarbonate solution are added to the reactionmedium. After separating after settling out, the organic [lacuna] isdried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 63 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazineare thus obtained in the form of a beige lacquer [¹H NMR spectrum (400MHz, CDCl₃), □ in ppm): 0.92 (d, J=7 Hz, 6H), 1.82 (mt, 1H), 2.14 (d,J=8 Hz, 2H), 2.54 (t, J=5.5 Hz, 4H), 2.75 (s, 3H), 3.18 (t, J=5.5 Hz,4H), 3.81 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.78 (d, J=8 Hz, 1H),6.89 (dd, J=8 and 2.5 Hz, 1H), 6.97 (broad s, 1H), from 7.15 to 7.30(mt, 5H), 7.32 (d, J=8 Hz, 4H)].

EXAMPLE 152

32 mg of sodium acetoxyborohydride and then 13 mg of acetaldehyde aresuccessively added, at a temperature close to 20° C., to a solution of54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazinein 2 cm³ of 1,2-dichloromethane. After stirring for 21 hours at atemperature close to 20° C., 2 cm³ of a saturated aqueous sodiumbicarbonate solution are added to the reaction mixture. After separatingafter settling out, the aqueous phase is reextracted with 2 cm³ ofdichloromethane. The pooled organic phases are dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure (1kPa) at a temperature close to 20° C. 60 mg of a solid residue are thusobtained, which residue is taken up in 2 cm³ of methanol and 0.5 cm³ ofdichloromethane. The solution obtained is deposited on a silicacartridge (500 mg of SCX phase). The cartridge is washed with 5 cm³ ofmethanol and then the expected product is eluted with 5 cm³ ofammoniacal methanol (2 N) and then with an additional 5 cm³ of methanol.The filtrate is concentrated to dryness under reduced pressure (1kPa) ata temperature close to 30° C. 42 mg of[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-ethylpiperazineare thus obtained in the form of a colorless lacquer [¹H NMR spectrum(300 MHz, CDCl₃), □ in ppm): 1.14 (t, J=7.5 Hz, 3H), 2.48 (q, J=7.5 Hz,2H), 2.60 (broad t, J=5 Hz, 4H), 2.77 (s, 3H), 3.22 (broad t, J=5 Hz,4H), 3.82 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broad d, J=8 Hz,1H), 6.91 (dd, J=8 and 2 Hz, 1H), 6.98 (mt, 1H), from 7.20 to 7.40 (mt,9H)].

EXAMPLE 153

2 cm³ of pyridine and then 11.5 mg of acetic anhydride are successivelyadded, at a temperature close to 20° C., to 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 23 hours at a temperature close to 20° C., thereaction medium is concentrated to dryness under reduced pressure (1kPa) at a temperature close to 30° C. The residue obtained is taken upin 5 cm³ of ethyl acetate and 2 cm³ of water. After separating aftersettling out, the organic phase is washed with 2 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 52 mg of4-acetyl1-[3({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazineare thus obtained in the form of a beige foam [¹H NMR spectrum (300 MHz,CDCl₃), □ in ppm): 2.16 (s, 3H), 2.77 (s, 3H), from 3.10 to 3.25 (mt,4H), 3.63 (broad t, J=5.5 Hz, 2H), 3.78 (broad t, J=5.5 Hz, 2H), 3.82(mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (broad d, J=8 Hz, 1H), 6.92(dd, J=8 and 2 Hz, 1H), 7.02 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 154

511 mg of supported EDCI (2.5 mM) 11.5 mg of N,N-dimethylglycine andthen 5 cm³ of dichloromethane are successively added, at a temperatureclose to 20° C., to 54 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 24 hours at a temperature close to 20° C., 35 mg ofN,N-dimethylglycine are added. After stirring for 96 hours at atemperature close to 20° C., the reaction mixture is filtered onsintered glass. The resin is rinsed with three times 2.5 cm³ ofdichloromethane. The combined filtrates are washed with 10 cm³ of water,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (5 kPa) at a temperature close to 20° C. 53 mg of1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminomethanoneare thus obtained in the form of a beige foam [¹H NMR spectrum (400 MHz,(CD₃)₂SO-d6, □ in ppm): 2.20 (s, 6H), 2.94 (s, 3H), 3.12 (s, 2H), 3.16(mt, 4H), 3.58 (mt, 2H), 3.68 (mt, 2H), 3.80 (mt, 2H), 4.19 (mt, 2H),4.78 (s, 1H), 6.81 (broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd,J=8 and 2.5 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46(d, J=8 Hz, 4H)].

EXAMPLE 155

A solution of 320 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester in 5 cm³ of formic acid is stirred for 5 hours ata temperature close to 20° C., and then for 1 hour at a temperatureclose to 45° C. The reaction medium is concentrated to dryness underreduced pressure (5 kPa) at a temperature close to 30° C., taken up in20 cm³ of ethyl acetate and alkalinized with 10 cm³ of a saturatedaqueous sodium bicarbonate solution. After separating after setting out,the organic phase is washed with three times 10 cm³ of water, dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (1 kPa) at a temperature close to 40° C. The residue obtainedis purified by depositing, in solution in a minimum of dichloromethane,on a silica gel deposited on a plate [(gel 0.5 mm thick, 5 plates of20□20 cm, eluent: dichloromethane-methanol (80-20 by volume)]. The zonecorresponding to the adsorbed desired product, located with UV rays, isscraped and the silica recovered is washed on sintered glass with adichloromethane-methanol mixture (75-25 by volume). The filtrates arecombined and concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 30° C. 180 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazineare thus obtained in the form of a white powder [¹H NMR spectrum (300MHz, CDCl₃), □ in ppm): 2.77 (s, 3H), 3.05 (mt, 4H), 3.16 (mt, 4H), 3.81(mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broad d, J=8 Hz, 1H), 6.90(dd, J=8 and 2.5 Hz, 1H), 6.98 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].

4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 4starting with 1.32 g of4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)phenyl]piperazine]-1-carboxylicacid tert-butyl ester, 0.232 cm³ of methanesulfonyl chloride and 0.7333g of 4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.063-0.200 mm,diameter 2 cm, height 25 cm) at atmospheric pressure with adichloromethane-methanol mixture (99.5-0.5 by volume) as eluent andcollecting 15 cm³ fractions. The fractions containing the desiredproduct are combined and concentrated to dryness under reduced pressure(5 kPa) at a temperature close to 30° C. 0.86 g of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester is thus obtained in the form of a white foam [¹HNMR spectrum (400 MHz, CDCl₃), □ in ppm): 1.50 (s, 9H), 2.77 (s, 3H),3.14 (t, J=5 Hz, 4H), 3.57 (t, J=5 Hz, 4H), 3.81 (mt, 2H), 4.34 (mt,2H), 4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H),6.99 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, =8 Hz, 4H)].

4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 1starting with 0.886 g of4-(3-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tert-butylester, 0.765 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one and 1.72cm³ of a 1.6 M solution of n-butyllithium in hexane, 1.37 g of4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester are obtained in the form of a beige powder.

4-(3-Methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tert-butylester may be prepared in the following manner: on carrying out theoperation according to the procedure of Example 10 starting with 1.55 gof 4-(3-chloromethylphenyl)piperazine-1-carboxylic acid tert-butyl esterand 0.766 g of sodium methanesulfinate, 0.9 g of4-(3-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tert-butylester is obtained in the form of a beige powder.

4-(3-Chloromethylphenyl)piperazine-1-carboxylic acid tert-butyl estermay be prepared in the following manner: by reacting 16.4 g of4-(3-hydroxymethylphenyl)piperazine-1-carboxylic acid tert-butyl esterin 150 cm³ of dichloromethane, at a temperature close to 20° C., with 29cm³ of diisopropylethylamine and 8.7 cm³ of methanesulfonyl chloride, 15g of 4-(3-chloromethylphenyl)piperazine-1-carboxylic acid tert-butylester are obtained in the form of a beige powder after purification on achromatographic column (Silica 0.063-0.200 mm, diameter 6 cm, height 45cm, 100 cm³ fractions), eluting with dichloromethane.

4-(3-Hydroxymethylphenyl)piperazine-1-carboxylic acid tert-butyl estermay be prepared in the following manner: by reacting 15.8 g oftert-butyl esters of 4-(3-butoxycarbonylphenyl)piperazine-1-carboxylicand 4-(3-n-butyloxycarbonylphenyl)piperazine-1-carboxylic acids insolution in 500 cm³ of anhydrous THF, at a temperature close to −10° C.,with 102 cm³ of diisobutylaluminum hydride in solution in toluene (20%by weight), 12.8 g of 4-(3-hydroxymethylphenyl)piperazine-1-carboxylicacid tert-butyl ester are obtained in the form of a beige oil.

The mixture of tert-butyl esters of4-(3-ethoxycarbonylphenyl)piperazine-1-carboxylic and4-(3-n-butyloxycarbonylphenyl)piperazine-1-carboxylic acids may beprepared according to the method described in patent WO 9726250.

EXAMPLE 156

On carrying out the operation according to Example 38 (method 2)starting with 0.3 g of3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[93,5-difluorophenyl)(methylsulfonyl)methyl(RS)]azetidineand 105 mg of lithium hydroxide monohydrate in 10 cm³ of acetonitrile,at a temperature close to 70° C. 0.24 g of1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of an orange-colored foam [¹H NMR spectrum (300MHz, CDCl₃, □ in ppm): 2.81 (s, 3H), from 3.85 to 3.95 (mt, 2H), 3.89(s, 6H), 4.37 (mt, 2H), 4.67 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H),6.99 (mt, 2H), 7.50 (d, J=8 Hz, 4H), 7.97 (d, J=8 Hz, 4H)].

EXAMPLE 157

On carrying out the operation according to the procedure of Example 40starting with 4.45 g of (3,5-difluorobenzyl)methylsulfone, 6.36 g of1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-one, 2.18 cm³ of acetylchloride and 17 cm³ of a 1.6 M solution of n-butyllithium in hexane,10.8 g of3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl(RS)]azetidineare obtained in the form of a pale yellow foam [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, □ in ppm): 2.03 (s, 3H), 2.96 (s, 3H), from 3.25 to3.40 (mt, 2H), 3.52 (broad d, J=8 Hz, 1H), from 3.75 to 3.90 (mt, 1H),3.82 (s, 3H), 3.83 (s, 3H), 4.72 (s, 1H), 5.36 (s, 1H), 7.27 (d, J=8 Hz,2H), from 7.35 to 7.45 (mt, 2H), 7.43 (d, J=8 Hz, 2H), 7.54 (tt, J=9.5and 2.5 Hz, 1H), 7.81 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H)].

1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-one may be prepared inthe same manner as1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one(Example 110) from 1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-ol.

1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-ol, may be prepared inthe same manner as1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol(Example 110)from bis(4-methoxycarbonylphenyl)methylamine.

Bis(4-methoxycarbonylphenyl)methylamine may be prepared in the samemanner as methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate (Example87) from 4,4′-dimethoxycarbonylbenzophenone.

EXAMPLE 158

On carrying out the operation according to the procedure of Example 110starting with 40 mg of(RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidine,0.25 cm³ of dichloromethane and 0.0196 cm³ of morpholine, 35.8 mg of(RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)methanesulfonylmethylene]azetidin-1-yl}methyl)benzyl]morpholineare obtained in the form of a white foam [¹H NMR spectrum (400 MHz,CDCl₃, □ in ppm): 2.41 (mt, 4H), 2.80 (s, 3H), 3.42 (s, 2H), 3.69 (t,J=4.5 Hz, 4H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

(RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidinemay be prepared in the following manner: on carrying out the operationaccording to Example 87 starting with 415 mg of(RS)-1-[(4-(chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,5 cm³ of dichloromethane, 0.19 cm³ of methanesulfonyl chloride and 0.53cm³ of diisopropylethylamine, 421.2 mg of(RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidineare obtained in the form of a cream-colored foam.

EXAMPLE 159

25 mg of potassium carbonate and then 0.016 cm³ of morpholine aresuccessively added, at a temperature close to 20° C., under an inertatmosphere of argon, to a solution of 33 mg of1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidinein 2 cm³ of anhydrous acetonitrile. After stirring for 17 hours at atemperature close to 20° C., the reaction medium is diluted with 10 cm³of ethyl acetate and 4 cm³ of water. The separated organic phase iswashed with 4 cm³ of a saturated aqueous sodium chloride solution, driedover magnesium sulfate, filtered on sintered glass and then concentratedto dryness under reduced pressure (1 kPa) at a temperature close to 4°C. The residue obtained is purified by depositing, in solution in aminimum of dichloromethane, on chromatography on silica gel deposited ona plate [(gel 0.5 mm, thick, 2 plates of 20□20 cm, eluent:dichloromethane-methanol (92.5-7.5 by volume)]. The zone correspondingto the desired product adsorbed, located with UV rays, is scraped andthe silica recovered is washed on sintered glass with adichloromethane-methanol mixture (80-20 by volume). The filtrates arecombined and concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 40° C. 25.2 mg of4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}butyl)morpholineare obtained in the form of a pale yellow foam [¹H NMR spectrum (400MHz, CDCl₃, □ in ppm): 1.66 (mt, 2H), 1.81 (mt, 2H), 2.40 (t, J=7.5 Hz,2H), 2.46 (mt, 4H), 2.77 (s, 3H), 3.72 (t, J=5 Hz, 4H), 3.84 (mt, 2H),3.96 (t, J=6.5 Hz, 2H), 4.36 (mt, 2H), 4.53 (s, 1H), 6.87 (dd, J=8 and 2Hz, 1H), 6.93 (d, J=8 Hz, 1H), 6.96 (d, J=2 Hz, 1H), from 7.10 to 7.35(mt, 7H), 7.42 (d, J=8 Hz, 4H)].

1-Benzhydryl-3-{[(3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidinemay be prepared in the following manner: 0.586 cm³ of 1,4-dibromobutaneand 255 mg of potassium carbonate are successively added at atemperature close to 20° C., under an inert atmosphere of argon, to asolution of 500 mg of1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine in10 cm³ of methylethyl ketone. The reaction mixture is heated at thereflux temperature of the solvent, under an inert atmosphere of argon,for 7 hours and then left at a temperature close to 20° C. for about 4days. The reaction mixture is filtered on sintered glass covered withcelite. The solid residue is rinsed with ethyl acetate and then thefiltrate is concentrated to dryness under reduced pressure (10 kPa) at atemperature close to 40° C. The brown oil obtained is purified bychromatography at atmospheric pressure on 40 g of silica (0.063-0.200mm) contained in a column 3 cm in diameter, eluting with amethanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10cm³) containing only the desired product are combined and concentratedto dryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours,408.4 mg of1-benzydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidineare thus obtained in the form of a brown foam.

EXAMPLE 160

0.110 cm³ of morpholine and then 35 mg of potassium carbonate aresuccessively added, at a temperature close to 20° C., to a solution of45 mg of1-benzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}azetidinein 3.5 cm³ of anhydrous acetonitrile. After stirring for 20 hours at atemperature close to 20° C., the reaction medium is diluted with 40 cm³of ethyl acetate and 10 cm³ of water. The separated organic phase iswashed with 10 cm³ of water, and then twice 10 cm³ of a saturatedaqueous sodium chloride solution, dried over magnesium sulfate, filteredon sintered glass and then concentrated to dryness under reducedpressure (9 kPa) at a temperature close to 40° C. The yellow lacquerobtained is purified by depositing, in solution in a minimum ofdichloromethane, on chromatography on silica gel deposited on a plate[(gel 0.5 mm thick, 2 plates of 20□20 cm, eluent:dichloromethane-methanol (97.5-2.5 by volume)]. The zone correspondingto the desired product adsorbed, located with UV rays, is scraped andthe silica recovered is washed on sintered glass with adichloromethane-methanol mixture (85-15 by volume). The filtrates arecombined and concentrated to dryness under reduced pressure (1kPa) at atemperature close to 4° C. 33 mg of4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholineare thus obtained in the form of a white foam [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d6, □ in ppm): 1.87 (mt, 2H), 2.37 (mt, 4H), 2.42 (t, J=7.5 Hz,2H), 2.94 (s, 3H), 3.58 (mt, 4H), 3.80 (mt, 2H), 4.02 (t, J=7 Hz, 2H),4.20 (mt, 2H), 4.74(s, 1H), 6.97 (mt, 3H), 7.22 (t, J=7.5 Hz, 2H), from7.25 to 7.40 (mt, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz, 4H)].

1-Benzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}azetidinemay be prepared in the following manner: 0.5 cm³ of 1,3-dibromopropaneand 255 mg of potassium carbonate are successively added at atemperature close to 20° C., under an inert atmosphere of argon, to asolution of 500 mg of1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine in10 cm³ of methyl ethyl ketone. The reaction mixture is heated at thereflux temperature of the solvent, under an inert atmosphere of argon,for 7 hours, and then left at a temperature close to 20° C. for about 4days. The reaction mixture is filtered on sintered glass covered withcelite. The solid residue is rinsed with ethyl acetate and then thefiltrate is concentrated to dryness under reduced pressure (10 kPa) at atemperature close to 40° C. The brown oil obtained is purified bychromatography at atmospheric pressure on 40 g of silica (0.063-0.200mm) contained in a column 3 cm in diameter, eluting with amethanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10cm³) containing only the desired product are combined and concentratedto dryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours.511.1 mg ofbenzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}azetidineare thus obtained in the form of a brown foam.

The medicaments according to the invention consists of a compound offormula (I) or an isomer or a salt of such a compound, in the pure stateor in the form of a composition in which it is combined with any otherpharmaceutically compatible product which may be inert orphysiologically active. The medicaments according to the invention maybe used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders(gelatine capsules, sachets) or granules may be used. In thesecompositions, the active ingredient according to the invention is mixedwith one or more inert diluents, such as starch, cellulose, sucrose,lactose or silica, under an argon stream. These compositions may alsocomprise substances other than diluents, for example one or morelubricants such as magnesium stearate or talc, a coloring, a coating(sugar-coated tablet) or a glaze.

As liquid compositions for oral administration, there may be usedpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents such as water, ethanol, glycerol,vegetable oils or paraffin oil. These compositions may comprisesubstances other than diluents, for example wetting, sweetening,thickening, flavoring or stabilizing products.

Sterile compositions for parenteral administration may be preferablysolutions which are aqueous or nonaqueous, suspensions or emulsions. Assolvent or vehicle, there may be used water, propylene glycol,polyethylene glycol, vegetable oils, in particular olive oil, injectableorganic esters, for example ethyl oleate or other suitable organicsolvents. These compositions may also contain adjuvants, in particularwetting, isotonizing, emulsifying, dispersing and stabilizing agents.Sterilization may be carried out in several ways, for example byaseptisizing filtration, by incorporating sterilizing agents into thecomposition, by irradiation or by heating. They may also be prepared inthe form of sterile solid compositions which may be dissolved at thetime of use in sterile water or any other injectable sterile medium.

Compositions for rectal administration are suppositories or rectalcapsules which contain, in addition to the active product, excipientssuch as cocoa butter, semisynthetic glycerides or polyethylene glycols.

Compositions for topical administration may be, for example, creams,lotions, collyria, collutoria, nasal drops or aerosols.

In human therapy, the compounds according to the invention areparticularly useful for the treatment and/or prevention of psychosesincluding schizophrenia, anxiety disorders, depression, epilepsy,neurodegeneration, cerebellar and spinocerebellar disorders, cognitivedisorders, cranial trauma, panic attacks, peripheral neuropathies,glaucomas, migraine, Parkinson's disease, Alzheimer's disease,Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsivedisorder, senile dementia, thymic disorders, Tourette's syndrome,tardive dyskinesia, bipolar disorders, cancers, movement disordersinduced by medicaments, dystonia, endotoxemic shocks, hemmorhagicshocks, hypotension, insomnia, immunological diseases, multiplesclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia),obesity, memory disorders, intestinal transit disorders, in weaning fromchronic treatments and alcohol or drug abuse (opiods, barbiturates,cannabis, cocaine, amphetamine, phencyclide, hallucinogens,benzodiazepines for example), as analgesics or potentiators of theanalgesic activity of the narcotic and nonnarcotic drugs asantibacterial, antiviral and antiparasitic agents.

The doses depend on the desired effect, the duration of the treatmentand the route of administration used; they are generally between 5 mgand 1000 mg per day orally for an adult with unit doses ranging from 1mg to 250 mg of active substance.

In general, the doctor will determine the appropriate dosage dependingon the age, weight and any other factors specific to the subject to betreated.

The following examples illustrate the compositions according to theinvention:

EXAMPLE A

Gelatin capsules containing a dose of 50 mg of active product and havingthe following composition are prepared according to the usual technique:

-   -   Compound of formula (I) 50 mg    -   Cellulose 18 mg    -   Lactose 55 mg    -   Colloidal silica 1 mg    -   Sodium carboxymethylstarch 10 mg    -   Talc 10 mg    -   Magnesium stearate 1 mg

EXAMPLE B

Tables containing a doze of 50 mg of active product and having thefollowing composition are prepared according to the usual technique:

-   -   Compound of formula (I) 50 mg    -   Lactose 104 mg    -   Cellulose 40 mg    -   Polyvidone 10 mg    -   Sodium carboxymethylstarch 22 mg    -   Talc 10 mg    -   Magnesium stearate 2 mg    -   Colloidal silica 2 mg    -   Mixture of hydroxymethylcellulose, glycerin, titanium oxide        (72-3.5-24.5) qs 1 finished film-coated tablet containing 245 mg

EXAMPLE C

An injectable solution containing 10 mg of active product and having thefollowing composition is prepared:

-   -   Compound of formula (I) 10 mg    -   Benzoic acid 80 mg    -   Benzyl alcohol 0.06 mg    -   Sodium benzoate 80 mg    -   Ethanol, 95% 0.4 ml    -   Sodium hydroxide 24 mg    -   Propylene glycol 1.6 ml    -   Water qs 4 ml

1. A method of treating a condition selected from the group consistingof schizophrenia, Parkinson's disease, and Alzeimer's disease, thismethod comprising administering to a patient in need of such treatmentan effective amount to treat said condition of a compound of formula:

R₁ represents a methyl or ethyl radical, R₂ represents either anaromatic chosen from phenyl, naphthyl and indenyl, these aromatics beingnonsubstituted or substituted with one or more substituents selectedfrom halogen, alkyl, alkoxy, —CO-alk, hydroxyl, —COOR₅, formyl,trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,—NR₆R₇, —CO—NH—NR₆R₇, —N(alk)COOR₈, cyano, —CONHR₉, —CO—NR₁₆R₁₇,alkylsulfanyl, hydroxyalkyl, —O-alk-NR₁₂R₁₃ and alkylthioalkyl or aheteroaromatic radical selected from benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl,pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,1,2,3,4-tetrahydroquinolyl, thiazolyl, and thienyl, these heteroaromaticradicals being nonsubstituted or substituted with a substituent selectedfrom halogen, alkyl, alkoxy, —COOR₅, trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, nitro, —NR₆R₇, —CO—NH—NR₆R₇,cyano, —CONHR₉, alkylsulfanyl, hydroxyalkyl and alkylthioalkyl; R₃ andR₄, which are identical or different, each represent either an aromaticradical selected from phenyl, naphthyl and indenyl, these aromaticradicals being nonsubstituted or substituted with one or moresubstituents selected from halogen, alkyl, alkoxy, formyl, hydroxyl,trifluoromethyl, trifluoromethoxy, nitro, —CO-alk, cyano, —COOR₅,—CONR₁₀R₁₁, —CO—NH—NR₆R₇, alkylsulfanyl, hydroxyalkyl, -alk-NR₆R₇ andalkylthioalkyl; or a heteroaromatic radical selected from benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromanyl,isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,thiazolyl and thienyl, these heteroaromatics being nonsubstituted orsubstituted with a substituent selected from halogen, alkyl, alkoxy,hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, —COOR₅,—CO—NH—NR₆R₇, —CONR₁₀R₁₁,-alk-NR₆R₇, alkylsulfanyl, hydroxyalkyl andalkylthioalkyl; R₅ is an alkyl or phenyl radical which is optionallysubstituted with one or more halogens; R₆ and R₇, which are identical ordifferent, represent a hydrogen atom or an alkyl, —COOalk, cycloalkyl,alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or, alternatively,R₆ and R₇ together with the nitrogen atom to which they are attached,form a 3- to 10-membered saturated or unsaturated mono- or bicyclicheterocycle optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with one ormore alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo,hydroxyalkyl, -alk-O-alk or —CO—NH₂ radicals; R₈ represents an alkylradical; R₉ represents a hydrogen or unsubstituted alkyl radical or analkyl radical that is substituted with a dialkylamino, phenyl,cycloalkyl (optionally substituted with —COOalk) or a 3- to 10-memberedsaturated or unsaturated mono- or bicyclic heterocycle containing one ormore heteroatoms chosen from oxygen, sulfur and nitrogen and beingoptionally substituted with one ore more alkyl radicals; R₁₀ and R₁₁,which are identical or different, each represent a hydrogen atom or analkyl radical or, alternatively, R₁₀ and R₁₁ together with the nitrogenatom to which they are attached, form a 3- to 10-membered saturatedmono- or bicyclic heterocycle optionally containing another heteroatomselected from oxygen, sulfur and nitrogen and being and are optionallysubstituted with an alkyl radical; R₁₂ and R₁₃, which are identical ordifferent, represent a hydrogen, alkyl or cycloalkyl radical or,alternatively, R₁₂ and R₁₃, together with the nitrogen atom to whichthey are attached, form a 3- to 10-membered saturated mono- or bicyclicheterocycle optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with analkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk or —CO-alk-NR₁₄R₁₅ radical,or a 3- to 10-membered saturated mono- or bicyclic heterocyclecontaining a heteroatom chosen from oxygen, sulfur and nitrogen; R₁₄ andR₁₅, which are identical or different, represent a hydrogen, alkyl or—COOalk radical; R₁₆ and R₁₇, together with the nitrogen atom to whichthey are attached, form a 3- to 10-membered saturated mono- or bicyclicheterocycle optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen; R′ represents a hydrogen or —CO-alkradical; alk represents an alkyl or alkylene radical, it beingunderstood that the alkyl and alkylene radicals and portions and thealkoxy radicals and portions are in the form of a straight or branchedchain and contain 1 to 6 carbon atoms, or an optional isomer thereof ora salt thereof with an inorganic or organic acid.
 2. The method of claim1 wherein, in the compound of formula (I) according to claim 1, when R₆and R₇, together with the nitrogen atom to which they are attached, forma 3- to 10-membered saturated or unsaturated mono- or bicylicheterocycle, the latter is an azetidinyl, pyrrolidinyl, piperazinyl,piperidyl, morpholinyl, imidazolyl, thiomorpholinyl or furyl ring, theserings being optionally substituted with an alkyl, hydroxyalkyl,-alk-O-alk, —CONH₂, —COalk, —COOalk, oxo, —CSNHalk, —CONHalk or—CO-alk-NR₁₄R₁₅ in which alk, R₁₄ and R₁₅ have the same meanings as inclaim 1, or an optical isomer thereof or a salt thereof with aninorganic or organic acid.
 3. The method of claim 1 wherein, in thecompound of formula (I) according to claim 1, when R₁₀ and R₁₁, togetherwith the nitrogen atom to which they are attached, form a 3- to10-membered saturated mono- or bicylic heterocycle, said heterocycle isan azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, orthiomorpholinyl ring, these rings being optionally substituted with analkyl.
 4. The method of claim 1 wherein, in the compound of formula (I)according to claim 1, when R₁₂ and R₁₃, together with the nitrogen atomto which they are attached, form a 3- to 10-membered saturated orunsaturated mono- or bicylic heterocycle, said heterocycle is selectedfrom azetidinyl, pyrrolidinyl, piperazinyl, piperazinyl, piperidyl,morpholinyl and thiomorpholinyl rings, these rings being optionallysubstituted with an alkyl, —COalk, —COOalk, —CONHalk or —CO-alk-NR₁₄R₁₅radical or a 3- 10-membered saturated mono- or bicyclic heterocyclecontaining a heteroatom selected from oxygen, sulfur and nitrogen, alk,R₁₄ and R₁₅ having the same meanings as in claim 1, an optical isomerthereof, or a salt thereof with an inorganic or organic acid.
 5. Themethod of claim 4 wherein said heterocycle is a thiomorpholinyl radical.6. The method of claim 1 wherein, in the compound of formula (I)according to claim 1, where R₁₆ and R₁₇, together with the nitrogen atomto which they are attached, form a 3- to 10-membered saturated mono- orbicyclic heterocycle, said heterocycle is a piperidyl ring, or anoptical isomer thereof or a salt thereof with an inorganic or organicacid.
 7. The method of claim 1 wherein, in the compound of formula (I)according to claim 1, R₉ is an alkyl radical substituted with a 3- to10-membered saturated or unsaturated mono- or bicyclic heterocycleselected from pyrrolidinyl, tetrahydrofuryl, morpholinyl and pyrrolylrings, these rings being optionally substituted with one or more alkylradicals, an optical isomer thereof or a salt thereof with an inorganicor organic acid.
 8. The method of claim 1 wherein, in the compound offormula (I) according to claim 1, R represents structure (A) or (B); R′represents a hydrogen atom or a —COalk radical; R₁ represents a methylor ethyl radical; R₂ represents either an aromatic radical selected fromphenyl and naphthyl, these aromatic radicals being nonsubstituted orsubstituted with one or more substituents selected from halogen, alkyl,alkoxy, hydroxyl, —COOR₅, trifluoromethyl, trifluoromethylsulfanyl,trifluoromethoxy, —NR₆R₇, —CO—NH—NR₆R₇, cyano, —CONHR₉, alkylsulfanyl,hydroxyalkyl, nitro, —CO—NR₁₆R₁₇, —O-alkNR₁₂R₁₃ and alkylthioalkyl, or aheteroaromatic radical selected from isoquinolyl, pyridyl, quinolyl,1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl and thienyl,these heteroaromatic radicals being unsubstituted or substituted with ahalogen, alkyl, alkoxy, —COOR₅, trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇, —CO—NH—NR₆R₇, cyano,—CONHR₉, alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkylsubstituent; R₃ and R₄, which may be identical or different, representeither an aromatic radical selected from phenyl and naphthyl, thesearomatic radicals being nonsubstituted or substituted with one or moresubstituents selected from halogen, alkyl, alkoxy, trifluoromethyl,trifluoromethoxy, —CONR₁₀R₁₁, -alk-NR₆R₇, hydroxyalkyl, formyl and—COOR₅, or a heteroaromatic radical selected from thiazolyl or thienylrings, these heteroaromatics being nonsubstituted or substituted by ahalogen, alkyl, alkoxy, —CONR₁₀R₁₁, -alk-NR₆R₇, hydroxyalkyl or —COOR₅;R₅ is alkyl or phenyl which is optionally substituted with one or morehalogens; R₆ and R₇, which may be identical or different, represent ahydrogen, alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk orhydroxyalkyl radical or, alternatively, R₆ and R₇, together with thenitrogen atom to which they are attached, form a 3- to 10-memberedsaturated or unsaturated mono- or bicyclic heterocycle optionallycontaining another heteroatom chosen from oxygen, sulfur and nitrogenand being optionally substituted with one or more alkyl, —COalk,—COOalk, —CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo, hydroxyalkyl,alk-O-alk or —CO—NH₂ radicals; R₉ represents a hydrogen atom orunsubstituted alkyl radical or an alkyl radical substituted withdialkylamino, phenyl, cycloalkyl (optionally substituted with —COOalk)or a 3- to 10-membered saturated or unsaturated mono- or bicyclicheterocycle containing one or more heteroatoms chosen from oxygen,sulfur and nitrogen and being optionally substituted with one ore morealkyl radicals; R₁₀ and R₁₁, which may be identical or different,represent a hydrogen or alkyl radical or, alternatively, R₁₀ and R₁₁,together with the nitrogen atom to which they are attached, form a 3- to10-membered saturated mono- or bicyclic heterocycle optionallycontaining another heteroatom chosen from oxygen, sulfur and nitrogenand being optionally substituted with an alkyl radical; R₁₂ and R₁₃,which may be identical or different, represent a hydrogen, alkyl orcycloalkyl radical or, alternatively, R₁₂ and R₁₃, together with thenitrogen atom to which they are attached, form a 3- to 10-memberedsaturated mono- or bicyclic heterocycle optionally containing anotherheteroatom chosen from oxygen, sulfur and nitrogen and being optionallysubstituted with an alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk or—CO-alk-NR₁₄R₁₅ radical, or a 3- to 10-membered saturated mono- orbicyclic heterocycle containing a heteroatom chosen from oxygen, sulfurand nitrogen; R₁₄ and R₁₅, which may be identical or different,represent a hydrogen, alkyl or —COOalk radical; R₁₆ and R₁₇, togetherwith the nitrogen atom to which they are attached, form a 3- to10-membered saturated mono- or bicyclic heterocycle optionallycontaining another heteroatom chosen from oxygen, sulfur and nitrogen;alk represents an alkyl or alkylene radical, it being understood thatthe alkyl and alkylene radicals and portions and the alkoxy radicals andportions are in the form of a straight or branched chain and contain 1to 6 carbon atoms, an optical isomer thereof or a salt thereof with aninorganic or organic acid.
 9. The method of claim 1 wherein saidcompound is selected from:1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,3-acetoxy-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethyl-(RS)]azetidine,their optical isomers and their salts with an inorganic or organic acid.10. The method of claim 1 wherein, in the compound of formula (I)according to claim 1, R represents structure (A) or (B); R′ representinga hydrogen or —COalk radical; R₁ represents a methyl or ethyl radical;R₂ represents either (I) an aromatic selected from naphthyl, phenyl,phenyl substituted with one or more halogen, alkyl, alkoxy, hydroxyl,—COOR₅ (in which R₅ represents an alkyl or phenyl radical optionallysubstituted with several halogens) trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇ (in which R₆ and R₇,which may be identical or different, represent a hydrogen, alkyl or—COOalk radical or, alternatively, R₆ and R₇, together with the nitrogenatom to which they are attached, form a heterocycle selected frompyrrolidinyl, piperidyl, piperazinyl and piperazinyl substituted withone or more alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk or—CO-alk-NR₁₄R₁₅ radicals (in which R₁₄ and R₁₅, which may be identicalor different, represent a hydrogen or alkyl radical), —CO—NH—NR₆R₇(inwhich R₆ and R₇, which may be identical or different, represent ahydrogen or alkyl radical or, alternatively, R₆ and R₇ together with thenitrogen atom to which they are attached, form a heterocycle selectedfrom piperidyl, pyrrolyl, piperazinyl and piperazinyl substituted withone or more alkyl radicals), cyano, —CONHR₉ (in which R₉ represents ahydrogen or unsubstituted alkyl radical or an alkyl radical substitutedwith dialkylamino, phenyl or cycloalkyl (optionally substituted with—COOalk) or (II) a heterocycle selected from pyrrolidinyl (optionallysubstituted with alkyl), tetrahydrofuryl, or morpholinyl),alkylsulfanyl, hydroxyalkyl, nitro, —CO—NR₁₆R₁₇, (in which R₁₆ and R₁₇,together with the nitrogen atom to which they are attached, form apiperidyl ring), —O-alkNR₁₂R₁₃ (in which R₁₂ and R₁₃, together with thenitrogen atom to which they are attached, form a morpholino ring) andalkylthioalkyl, or (III) a heteroaromatic selected from isoquinolyl,pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,1,2,3,4-tetrahydroquinolyl, and thienyl substituted with a —COOR₅ (inwhich R₅ represents an alkyl radical) or —CONHR₉, (in which R₉represents an alkyl radical); R₃ and R₄, which may be identical ordifferent, represent either (IV) an aromatic selected from phenyl andphenyl substituted with one or more substituents selected from halogen,alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl,—COOR₅ (in which R₅ is an alkyl radical), —CONR₁₀R₁₁ (in which R₁₀ andR₁₁, which may be identical or different, represent a hydrogen or alkylradical), -alk-NR₆R₇ (in which R₆ and R₇, which may be identical ordifferent, represent a hydrogen, alkyl, cycloalkyl, -alk-O-alk orhydroxyalkyl radical or, alternatively, R₆ and R₇, together with thenitrogen atom to which they are attached, form a heterocycle selectedfrom piperidyl (optionally substituted with alkyl or oxo), pyrrolidinyl(optionally substituted with alkyl, hydroxyalkyl, -alk-O-alk or—CO—NH₂), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl optionallysubstituted with oxo, alkyl, hydroxyalkyl, and —COOR₅ (in which R₅ is analkyl radical), or (V) a heteroaromatic selected from thiazolyl andthienyl; alk represents an alkyl or alkylene radical, it beingunderstood that the alkyl and alkylene radicals and portions and thealkoxy radicals and portions are in the form of a straight or branchedchain and contain 1 to 6 carbon atoms, an optical isomer thereof or asalt thereof with an inorganic or organic acid.
 11. The method of claim1 wherein said compound is selected from:1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine,1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidine,1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetidine,1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidine,1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,(R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,(S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,and1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis(trifluorophenyl)-phenyl]methylsulfonylmethylene}azetidine.12. The method of claims 1, wherein said compound is selected from:1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl]methylsulfonylmethylene}azetidine,(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-{(4-chlorophenyl)[4-pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,and1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,their optical isomers and their salts with an inorganic or organic acid.13. The method of claim 1, wherein said compound is selected from:1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{{(RS)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,their optical isomers and their salts with an inorganic or organic acid.14. The method of claim 1, wherein said compound is selected from:1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,their optical isomers and their salts with an inorganic or organic acid.15. The method of claim 1, wherein said compound is selected from:1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)]-(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-methylsulfonyl)(3-pyrrolidinylphenyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethyl-phenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)-methylene]azetidine,1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,(RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamoyl]phenyl}(methylsulfonyl)methylene}azetidine,1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)phenyl](methylsulfonyl)methylene}azetidine,1-[bis(thien-2yl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(p-tolyl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,1-[4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine,and(RS)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine,their optical isomers and their salts with an inorganic or organic acid.16. The method of claim 1, wherein said compound is selected from:1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS)azetidin-3-ol,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)methyl-(RS)azetidin-3-ol,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-morpholin-4-yl-propyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-piperidin-1-ylbenzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-isobutylbenzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylaminoethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid N′-methylhydrazide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclohexylmethylbenzamide,and3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclopropylmethylbenzamide,their optical isomers and their salts with an inorganic or organic acid.17. The method of claim 1, where said compound is selected from:3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-methylbutyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-phenylpropyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide,4-{[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylicacid methyl ester,2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonymethyl)phenyl]piperazin-1-yl}ethanone,(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamicacid tert-butyl ester,1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone,(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]piperazine-1-carbothioicacid N-methylamide,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]piperazine-1-carboxylicacid N-methylamide,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]piperazine-1-carboxylicacid methyl ester,1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]-4-isobutylpiperazine,1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]-4-ethylpiperazine,4-acetyl1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]piperazine,1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone,1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]piperazine,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methaneslfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester,1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidine,(RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)methanesulfonylmethylene]azetidin-1-yl}methyl)benzyl]morpholine,and4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}butyl)morpholine,4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholine,their optical isomers and their salts with an inorganic or organic acid.